Method for assessing and treating or preventing impaired plasma polar lipid levels

ABSTRACT

The invention pertains to the use of a preparation for the manufacture of a composition for preventing or treating impaired plasma levels of one or more polar lipids such as phosphatidylcholines [PC] selected from the group consisting of phosphatidylcholine diacyl C36:6 [PC aa C36:6], phosphatidylcholine diacyl C38:0 [PC aa C38:0], phosphatidylcholine diacyl C38:6 [PC aa C38:6], phosphatidylcholine diacyl C40:6 [PC aa C40:6] and phosphatidylcholine acyl-alkyl C40:6 [PC ae C40:6] in a preclinical AD or MCI subject or a subject with a high likelihood of developing AD or MCI, and wherein said subject is administered with a composition comprising at least one, preferably at least two, most preferably all B vitamins selected from the group consisting of vitamin B6, vitamin B12 and vitamin B9.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation Application of U.S. patentapplication Ser. No. 15/303,592, filed Oct. 12, 2016, which is theNational Phase of International Patent Application No.PCT/NL2015/050244, filed Apr. 14, 2015, published on Oct. 22, 2015 as WO2015/160247 A1, which claims priority to European Patent Application No.14169740.9, filed May 23, 2014 and to International Patent ApplicationNo. PCT/NL2014/050233, filed Apr. 14, 2014. The contents of theseapplications are herein incorporated by reference in their entirety.

FIELD OF THE INVENTION

The invention is in the field of medical nutrition and more particularlyrelates to a composition for use in preventing or treating impairedplasma polar lipid levels, preferably specific phosphatidylcholine (PC)levels in a preclinical Alzheimer's Disease [AD] or mild cognitiveimpairment [MCI] subject or a subject with a high likelihood ofdeveloping AD or MCI.

BACKGROUND DESCRIPTION

In the art there is a need for detecting neurodegenerative disorders andparticularly AD already in pre-clinical stages, before AD symptoms suchas cognitive dysfunction can be diagnosed. Amyloid plaques andneurofibrillary tangles, the neuropathological hallmarks of AD, are notlimited to individuals with dementia. Preclinical subjects alsoencompass those not suffering from amyloid plaques or neurofibrillarytangles. Pathologic changes can also be present in the brains ofcognitively normal older adults—a condition that is commonly defined aspreclinical AD. Similar definitions hold for preclinical MCI. Referenceis made to Sperling et al. “Toward defining the preclinical stages ofAlzheimer's disease: Recommendations from the National Institute onAging—Alzheimer's Association workgroups on diagnostic guidelines forAlzheimer's disease” Alzheimer's & Dementia 9 (2011) 280-292; thecontents hereof incorporated by reference. This way such subjects couldspecifically be targeted at much earlier stages. The art is searchingfor ways to identify and treat such preclinical subjects as early aspossible.

Subjects, including preclinical AD or MCI subjects, suffering fromimpaired plasma polar lipid levels, preferably PC levels have anextremely high likelihood of developing mild cognitive impairment andAlzheimer's Disease. For some phospholipids, impaired levels can beassociated with a 90% likelihood of developing such pathologicalconditions, long before symptoms such as cognitive dysfunction couldeven be diagnosed.

Advantageously, monitoring for changes in plasma phospholipid levels,preferably PC levels does not require any tedious brain imagingtechniques such as electroencephalography (EEG).

SUMMARY OF THE INVENTION

Through clinical studies the inventors established a set of biomarkersof plasma polar lipid species, preferably phosphatidylcholine [PC]species, which help identifying subjects suffering from impaired levelsof these plasma phospholipids, at the basis of which impairedphospholipid levels a subject can be identified having an extremely highlikelihood of developing MCI and AD. These biomarkers are thus reliablypredictive for conversion of a subject to MCI and AD, and helpidentifying ant treating preclinical MCI and AD subjects.

In addition, the inventors found that impaired plasma phospholipidlevels could be normalized using B vitamins only. Also, B vitaminshelped preventing the plasma levels of a set of polar lipids, preferablya set of phospholipids from changing. In a further intervention study of24 weeks involving administration of a product comprising B vitamins toa subject suffering from mild AD it was found that impaired plasmaphospholipid levels could be normalized.

In one leg of experiments, the biomarker panel of phospholipids studiedinvolved impaired plasma levels of phosphatidylcholine diacyl C36:6 [PCaa C36:6], phosphatidylcholine diacyl C38:0 [PC aa C38:0],phosphatidylcholine diacyl C38:6 [PC aa C38:6], phosphatidylcholinediacyl C40:6 [PC aa C40:6] and phosphatidylcholine acyl-alkyl C40:6 [PCae C40:6]. The increase in plasma levels of these phospholipids was mostprofound. In one aspect, the preferred targeted plasma polar lipidscomprise one or more selected from phosphatidylcholine species withmultiple double bonds, preferably selected from the group consisting of36:6, 38:6, 40:6, more preferably at least two of these polyunsaturatedPC species. The invention is particularly directed to treating orpreventing impaired plasma levels of at least PC aa 40:6 and/or PC ae40:6, most preferably at least PC aa 40:6.

In a second leg of experiments, the biomarker panel of phospholipidsstudied involved a more expanded set of plasma polar lipids alsoincluding phosphatidylcholine (PC) species, levels of which plasma polarlipid species were changed significantly through intervention with Bvitamins. For some, these effects were also confirmed using B vitaminsin combination with further components.

Based on all those experimental observations, the nutritionalintervention is believed useful in treating preclinical subjects withplasma lipid biomarker profiles predictive for conversion to preclinicalMCI or AD. The studies provided support that the plasma levels of aspecific set of phospholipids, as outlined in the application, areindicative of the changes taking place in the brains of cognitivelynormal older adults and prodromal AD or MCI subjects. The inventorsobserved that intervention with a composition comprising therapeuticallyeffective amounts of B vitamin(s) helped treating or restoring theseimpaired plasma polar lipid levels, and also helped preventing anundesired change of these plasma polar lipid levels in subjects prone todeveloping AD or MCI, particularly preclinical subjects. Preclinical MCIand preclinical AD subjects are defined in the art represented bySperling Alzheimer's & Dementia 9 (2011) 280-292, incorporated byreference. As evident from FIG. 3 therein, in the preclinical stages thesubject may be identified through all kinds of biomarkers but show lowcognitive dysfunction. These subjects have an increased likelihood ofdeveloping into MCI and AD subjects, accompanied from increasedcognitive dysfunction.

Based on the experimental findings presented herein it is concluded thata change of the plasma concentrations in each of the individual polarlipid species, particularly PC species is already indicative of animproved biomarker profile. It is not deemed necessary to monitor theplasma levels of each of these polar lipid species, particularly PCspecies in order to draw any conclusions on the extent of impairment andtreatment.

List of Preferred Embodiments I

1. Use of a preparation for the manufacture of a composition forpreventing or treating impaired plasma levels of one or morephosphatidylcholines [PC] selected from the group consisting ofphosphatidylcholine diacyl C36:6 [PC aa C36:6], phosphatidylcholinediacyl C38:0 [PC aa C38:0], phosphatidylcholine diacyl C38:6 [PC aaC38:6], phosphatidylcholine diacyl C40:6 [PC aa C40:6] andphosphatidylcholine acyl-alkyl C40:6 [PC ae C40:6] in a preclinical ADor MCI subject or a subject with a high likelihood of developing AD orMCI, and wherein said subject is administered with a compositioncomprising at least one, preferably at least two, most preferably all Bvitamins selected from the group consisting of vitamin B6, vitamin B12and vitamin B9.

2. Use according to embodiment 1, said composition comprising per dailydosage or per 100 ml, at least one, preferably at least two, mostpreferably all of:

0.5-10000 μg, preferably 0.5-1000 μg vitamin B12;0.5-100 mg, preferably 0.7-20 mg vitamin B6; and100-5000 μg, preferably 150-1000 μg folic acid.

3. Use according to embodiment 1 or 2, said composition comprising perdaily dosage or per 100 ml, 0.5-100 mg, preferably 0.7-20 mg vitamin B6,and 100-5000 μg, preferably 150-1000 μg folic acid.

4. Use according to any one of the preceding embodiments, wherein saidone or more phosphatidylcholines involve at least two, more preferablyat least three phosphatidylcholine species selected from the groupconsisting of phosphatidylcholine diacyl C36:6 [PC aa C36:6],phosphatidylcholine diacyl C38:0 [PC aa C38:0], phosphatidylcholinediacyl C38:6 [PC aa C38:6], phosphatidylcholine diacyl C40:6 [PC aaC40:6] and phosphatidylcholine acyl-alkyl C40:6 [PC ae C40:6].

5. Use according to any one of the preceding embodiments, wherein saidone or more phosphatidylcholine species is selected from the groupconsisting of phosphatidylcholine diacyl C36:6 [PC aa C36:6],phosphatidylcholine diacyl C38:6 [PC aa C38:6], phosphatidylcholinediacyl C40:6 [PC aa C40:6] and phosphatidylcholine acyl-alkyl C40:6 [PCae C40:6], preferably at least phosphatidylcholine diacyl C40:6 [PC aaC40:6] and/or phosphatidylcholine acyl-alkyl C40:6 [PC ae C40:6].

6. Use according to any of the preceding embodiments, wherein saidplasma PC levels are monitored in said subject before and/or afteradministration.

7. Use according to any one of the preceding embodiments, wherein saidcomposition further comprises one or more of uridine and cytidine, orsalts, phosphates, acyl derivatives or esters thereof.

8. A method for preventing or treating impaired plasma PC levels in apreclinical AD or MCI subject or a subject with a high likelihood ofdeveloping AD or MCI, comprising:

a) analyzing plasma levels of at least one phospholipid in a subject;b) selecting a subject having an impaired plasma level of one or more PCspecies selected from the group consisting of phosphatidylcholine diacylC36:6 [PC aa C36:6], PC aa C38:0, PC aa C38:6, PC aa C40:6 and PCacyl-alkyl C40:6 [PC ae C40:6];c) administering to said selected subject a composition comprising atleast one, preferably at least two, most preferably all B vitaminsselected from the group consisting of vitamin B6, vitamin B12 andvitamin B9, and optionally one or more of uridine and cytidine, orsalts, phosphates, acyl derivatives or esters thereof.

9. The method according to embodiment 8, wherein said plasma PC levelsare monitored after administration of said composition.

10. The method according to embodiment 8 or 9, wherein said subject isselected having impaired plasma levels of one or morephosphatidylcholine species selected from the group consisting ofphosphatidylcholine diacyl C36:6 [PC aa C36:6], phosphatidylcholinediacyl C38:6 [PC aa C38:6], phosphatidylcholine diacyl C40:6 [PC aaC40:6] and phosphatidylcholine acyl-alkyl C40:6 [PC ae C40:6],preferably at least phosphatidylcholine diacyl C40:6 [PC aa C40:6]and/or phosphatidylcholine acyl-alkyl C40:6 [PC ae C40:6].

11. Use or method according to any one of the preceding embodiments,wherein said composition further comprises a lipid fraction comprisingat least one of docosahexaenoic acid (22:6; DHA), eicosapentaenoic acid(20:5; EPA) and docosapentaenoic acid (22:5; DPA), or esters thereof.

12. Use or method according to any one of the preceding embodiments,wherein said composition further comprises, per daily dose or preferablyper 100 ml composition, at least 500 mg of DHA, preferably at least 600mg of DHA, and at least 50 mg of uridine, preferably at least 100 mg ofuridine.

13. Use or method according to any one of the preceding embodiments,wherein the composition comprises, per daily dose or preferably per 100ml composition:

0.5-10000 μg, preferably 0.5-1000 μg vitamin B12;0.5-100 mg, preferably 0.7-20 mg vitamin B6;100-5000 μg, preferably 150-1000 μg folic acid;100-500 mg, preferably 200-400 mg EPA,1000-1500 mg, preferably 1100-1300 mg DHA,50-600 mg, preferably 60-200 mg phospholipids,200-600 mg, preferably 300-500 mg choline,400-800 mg, preferably 500-700 mg UMP (uridine monophosphate),20-60 mg, preferably 30-50 mg vitamin E (alpha-TE),60-100 mg, preferably 70-90 mg vitamin C, and40-80 μg, preferably 50-70 μg selenium.

14. Use or method according to any one of the preceding embodiments,wherein the subject is an elderly of at least 50 years of age, and notsuffering from any cognitive deficits.

15. A composition for use in for preventing or treating impaired plasmalevels of one or more phosphatidylcholines [PC] selected from the groupconsisting of phosphatidylcholine diacyl C36:6 [PC aa C36:6],phosphatidylcholine diacyl C38:0 [PC aa C38:0], phosphatidylcholinediacyl C38:6 [PC aa C38:6], phosphatidylcholine diacyl C40:6 [PC aaC40:6] and phosphatidylcholine acyl-alkyl C40:6 [PC ae C40:6] in apreclinical AD or MCI subject or a subject with a high likelihood ofdeveloping AD or MCI, wherein said subject is administered with acomposition comprising at least one, preferably at least two, mostpreferably all B vitamins selected from the group consisting of vitaminB6, vitamin B12 and vitamin B9.

16. The composition for use according to embodiment 15, furthercomprising one or more of uridine and cytidine, or salts, phosphates,acyl derivatives or esters thereof.

17. The composition for use according to embodiment 15 or 16, whereinsaid one or more phosphatidylcholines involve at least two, morepreferably at least three phosphatidylcholine species selected from thegroup consisting of phosphatidylcholine diacyl C36:6 [PC aa C36:6],phosphatidylcholine diacyl C38:0 [PC aa C38:0], phosphatidylcholinediacyl C38:6 [PC aa C38:6], phosphatidylcholine diacyl C40:6 [PC aaC40:6] and phosphatidylcholine acyl-alkyl C40:6 [PC ae C40:6].

18. The composition for use according to any of embodiments 15-17,wherein said impaired plasma polar lipid levels involve impaired plasmalevels of at least one phosphatidylcholine species selected from thegroup consisting of PC aa C36:6, PC aa C38:6, PC aa C40:6 and PC aeC40:6, preferably at least PC aa C40:6 and/or PC ae C40:6.

List of Preferred Embodiments II

-   1. Use of a preparation for the manufacture of a composition for    preventing or treating impaired plasma levels of one or more polar    lipids selected from the group consisting of C16:1 CE; C18:3 CE;    C20:4 CE; PI(34:1); PI(38:2); PI(38:4); C16:0 CE; C18:2 CE;    PA(34:3); PE(36:0); PE(38:0); aePC(36:0); aePC(38:0); aePC(38:4);    aePC(40:4); 1PC(18:0); 1PC(18:3); 1PC(20:4); PC(36:1); PC(38:0);    PC(38:4); PC(40:4); DSM(18:0); aePC(32:1); aePC(32:2); aePC(34:0);    PC(44:2); SM(16:0); SM(18:0); SM(22:0); SM(24:0); SM(24:1);    aePC(36:5); aePC(38:5); aePC(40:5); 1PC(20:5); 1PC(22:5); PC(36:5);    PC(38:5); PC(40:5); PI(38:5); PI(40:5); C20:5 CE; C22:6 CE;    aePC(38:6); aePC(40:6); aePE(40:6); PC(36:6); PC(38:6); PC(40:6);    PC(42:6); PI(40:6); C22:5 CE; aePE(38:6); 1PE(22:6); PE(38:6);    PE(40:6); PI(38:6); PC(40:7); PC(40:8); PC(42:10); PC(42:7);    PC(42:8); PC(42:9); PE(40:7); 1PC(22:6); C19:0 CE; C19:1 CE; C20:0    CE; C20:1 CE; C20:3 CE; PE(34:1); PE(34:2); PE(36:1); PE(36:2);    PE(36:3); PE(36:4); PE(38:3); PE(38:4); PE(40:4); PI(36:3);    PI(38:3); PS(38:4); aePC(36:1); aePC(38:1); aePC(38:2); aePC(38:3);    aePC(40:2); aePC(40:3); 1PC(20:3); PC(34:3); PC(36:3); PC(38:1);    PC(38:2); PC(40:3); and PE(40:5) in a preclinical AD or MCI subject    or a subject with a high likelihood of developing AD or MCI, wherein    said composition comprises at least one, preferably at least two,    most preferably all B vitamins selected from the group consisting of    vitamin B6, vitamin B12 and vitamin B9.-   2. Use of a preparation for the manufacture of a composition for    preventing or treating impaired plasma levels of one or more    phosphatidylcholines [PC] selected from the group consisting of    phosphatidylcholine diacyl C36:6 [PC aa C36:6], phosphatidylcholine    diacyl C38:0 [PC aa C38:0], phosphatidylcholine diacyl C38:6 [PC aa    C38:6], phosphatidylcholine diacyl C40:6 [PC aa C40:6] and    phosphatidylcholine acyl-alkyl C40:6 [PC ae C40:6] in a preclinical    AD or MCI subject or a subject with a high likelihood of developing    AD or MCI, and wherein said subject is administered with a    composition comprising at least one, preferably at least two, most    preferably all B vitamins selected from the group consisting of    vitamin B6, vitamin B12 and vitamin B9.-   3. Use according to embodiment 1 or 2, said composition comprising    per daily dosage or per 100 ml, at least one, preferably at least    two, most preferably all of:    -   0.5-10000 μg, preferably 0.5-1000 μg vitamin B12;    -   0.5-100 mg, preferably 0.7-20 mg vitamin B6; and    -   100-5000 μg, preferably 150-1000 μg folic acid.-   4. Use according to embodiment 1-3, said composition comprising per    daily dosage or per 100 ml, 0.5-100 mg, preferably 0.7-20 mg vitamin    B6, and 100-5000 μg, preferably 150-1000 μg folic acid.-   5. Use according to embodiment 1 or 2, wherein the plasma polar    lipids are 1PC 22:6 and/or PC 40:6, preferably at least 1PC 22:6.-   6. Use according to any one of the preceding embodiments, wherein    said one or more phosphatidylcholines involve at least two, more    preferably at least three phosphatidylcholine species selected from    the group consisting of phosphatidylcholine diacyl C36:6 [PC aa    C36:6], phosphatidylcholine diacyl C38:0 [PC aa C38:0],    phosphatidylcholine diacyl C38:6 [PC aa C38:6], phosphatidylcholine    diacyl C40:6 [PC aa C40:6] and phosphatidylcholine acyl-alkyl C40:6    [PC ae C40:6].-   7. Use according to any one of the preceding embodiments, wherein    said one or more phosphatidylcholine species is selected from the    group consisting of phosphatidylcholine diacyl C36:6 [PC aa C36:6],    phosphatidylcholine diacyl C38:6 [PC aa C38:6], phosphatidylcholine    diacyl C40:6 [PC aa C40:6] and phosphatidylcholine acyl-alkyl C40:6    [PC ae C40:6], preferably at least phosphatidylcholine diacyl C40:6    [PC aa C40:6] and/or phosphatidylcholine acyl-alkyl C40:6 [PC ae    C40:6].-   8. Use according to any of the preceding embodiments, wherein said    plasma PC levels are monitored in said subject before and/or after    administration.-   9. Use according to any one of the preceding embodiments, wherein    said composition further comprises one or more of uridine and    cytidine, or salts, phosphates, acyl derivatives or esters thereof.-   10. A method for preventing or treating impaired plasma PC levels in    a preclinical AD or MCI subject or a subject with a high likelihood    of developing AD or MCI, comprising:    -   a) analyzing plasma levels of at least one phospholipid in a        subject;    -   b) selecting a subject having an impaired plasma level of one or        more PC species selected from the group consisting of        phosphatidylcholine diacyl C36:6 [PC aa C36:6], PC aa C38:0, PC        aa C38:6, PC aa C40:6 and PC acyl-alkyl C40:6 [PC ae C40:6];    -   c) administering to said selected subject a composition        comprising at least one, preferably at least two, most        preferably all B vitamins selected from the group consisting of        vitamin B6, vitamin B12 and vitamin B9, and optionally one or        more of uridine and cytidine, or salts, phosphates, acyl        derivatives or esters thereof.-   11. The method according to embodiment 10, wherein said plasma PC    levels are monitored after administration of said composition.-   12. The method according to embodiment 10 or 11, wherein said    subject is selected having impaired plasma levels of one or more    phosphatidylcholine species selected from the group consisting of    phosphatidylcholine diacyl C36:6 [PC aa C36:6], phosphatidylcholine    diacyl C38:6 [PC aa C38:6], phosphatidylcholine diacyl C40:6 [PC aa    C40:6] and phosphatidylcholine acyl-alkyl C40:6 [PC ae C40:6],    preferably at least phosphatidylcholine diacyl C40:6 [PC aa C40:6]    and/or phosphatidylcholine acyl-alkyl C40:6 [PC ae C40:6].-   13. Use or method according to any one of the preceding embodiments,    wherein said composition further comprises a lipid fraction    comprising at least one of docosahexaenoic acid (22:6; DHA),    eicosapentaenoic acid (20:5; EPA) and docosapentaenoic acid (22:5;    DPA), or esters thereof-   14. Use or method according to any one of the preceding embodiments,    wherein said composition further comprises, per daily dose or    preferably per 100 ml composition, at least 500 mg of DHA,    preferably at least 600 mg of DHA, and at least 50 mg of uridine,    preferably at least 100 mg of uridine.-   15. Use or method according to any one of the preceding embodiments,    wherein the composition comprises, per daily dose or preferably per    100 ml composition:    -   0.5-10000 μg, preferably 0.5-1000 μg vitamin B12;    -   0.5-100 mg, preferably 0.7-20 mg vitamin B6;    -   100-5000 μg, preferably 150-1000 μg folic acid;    -   100-500 mg, preferably 200-400 mg EPA,    -   1000-1500 mg, preferably 1100-1300 mg DHA,    -   50-600 mg, preferably 60-200 mg phospholipids,    -   200-600 mg, preferably 300-500 mg choline,    -   400-800 mg, preferably 500-700 mg UMP (uridine monophosphate),    -   20-60 mg, preferably 30-50 mg vitamin E (alpha-TE),    -   60-100 mg, preferably 70-90 mg vitamin C, and    -   40-80 μg, preferably 50-70 μg selenium.-   16. Use or method according to any one of the preceding embodiments,    wherein the subject is an elderly of at least 50 years of age, and    not suffering from any cognitive deficits.-   17. A composition for use in for preventing or treating impaired    plasma levels of one or more polar lipids selected from the group    consisting of C16:1 CE; C18:3 CE; C20:4 CE; PI(34:1); PI(38:2);    PI(38:4); C16:0 CE; C18:2 CE; PA(34:3); PE(36:0); PE(38:0);    aePC(36:0); aePC(38:0); aePC(38:4); aePC(40:4); 1PC(18:0);    1PC(18:3); 1PC(20:4); PC(36:1); PC(38:0); PC(38:4); PC(40:4);    DSM(18:0); aePC(32:1); aePC(32:2); aePC(34:0); PC(44:2); SM(16:0);    SM(18:0); SM(22:0); SM(24:0); SM(24:1); aePC(36:5); aePC(38:5);    aePC(40:5); 1PC(20:5); 1PC(22:5); PC(36:5); PC(38:5); PC(40:5);    PI(38:5); PI(40:5); C20:5 CE; C22:6 CE; aePC(38:6); aePC(40:6);    aePE(40:6); PC(36:6); PC(38:6); PC(40:6); PC(42:6); PI(40:6); C22:5    CE; aePE(38:6); 1PE(22:6); PE(38:6); PE(40:6); PI(38:6); PC(40:7);    PC(40:8); PC(42:10); PC(42:7); PC(42:8); PC(42:9); PE(40:7);    1PC(22:6); C19:0 CE; C19:1 CE; C20:0 CE; C20:1 CE; C20:3 CE;    PE(34:1); PE(34:2); PE(36:1); PE(36:2); PE(36:3); PE(36:4);    PE(38:3); PE(38:4); PE(40:4); PI(36:3); PI(38:3); PS(38:4);    aePC(36:1); aePC(38:1); aePC(38:2); aePC(38:3); aePC(40:2);    aePC(40:3); 1PC(20:3); PC(34:3); PC(36:3); PC(38:1); PC(38:2);    PC(40:3); and PE(40:5) in a preclinical AD or MCI subject or a    subject with a high likelihood of developing AD or MCI, and wherein    said subject is administered with a composition comprising at least    one, preferably at least two, most preferably all B vitamins    selected from the group consisting of vitamin B6, vitamin B12 and    vitamin B9.-   18. A composition for use in for preventing or treating impaired    plasma levels of one or more phosphatidylcholines [PC] selected from    the group consisting of phosphatidylcholine diacyl C36:6 [PC aa    C36:6], phosphatidylcholine diacyl C38:0 [PC aa C38:0],    phosphatidylcholine diacyl C38:6 [PC aa C38:6], phosphatidylcholine    diacyl C40:6 [PC aa C40:6] and phosphatidylcholine acyl-alkyl C40:6    [PC ae C40:6] in a preclinical AD or MCI subject or a subject with a    high likelihood of developing AD or MCI, wherein said subject is    administered with a composition comprising at least one, preferably    at least two, most preferably all B vitamins selected from the group    consisting of vitamin B6, vitamin B12 and vitamin B9.-   19. The composition for use according to embodiment 17 or 18,    further comprising one or more of uridine and cytidine, or salts,    phosphates, acyl derivatives or esters thereof.-   20. The composition for use according to embodiment 17-19, wherein    the plasma polar lipids are 1PC 22:6 and/or PC 40:6, preferably at    least 1PC 22:6.-   21. The composition for use according to embodiment 17-20, wherein    said one or more phosphatidylcholines involve at least two, more    preferably at least three phosphatidylcholine species selected from    the group consisting of phosphatidylcholine diacyl C36:6 [PC aa    C36:6], phosphatidylcholine diacyl C38:0 [PC aa C38:0],    phosphatidylcholine diacyl C38:6 [PC aa C38:6], phosphatidylcholine    diacyl C40:6 [PC aa C40:6] and phosphatidylcholine acyl-alkyl C40:6    [PC ae C40:6].-   22. The composition for use according to any of embodiments 17-21,    wherein said impaired plasma polar lipid levels involve impaired    plasma levels of at least one phosphatidylcholine species selected    from the group consisting of PC aa C36:6, PC aa C38:6, PC aa C40:6    and PC ae C40:6, preferably at least PC aa C40:6 and/or PC ae C40:6.-   23. A method for preventing or treating impaired plasma polar lipid    levels in a preclinical AD or MCI subject or a subject with a high    likelihood of developing AD or MCI, comprising:    -   a) analyzing plasma levels of at least one plasma polar lipid in        a subject, wherein said plasma polar lipid is selected from the        group consisting of C16:1 CE; C18:3 CE; C20:4 CE; PI(34:1);        PI(38:2); PI(38:4); C16:0 CE; C18:2 CE; PA(34:3); PE(36:0);        PE(38:0); aePC(36:0); aePC(38:0); aePC(38:4); aePC(40:4);        1PC(18:0); 1PC(18:3); 1PC(20:4); PC(36:1); PC(38:0); PC(38:4);        PC(40:4); DSM(18:0); aePC(32:1); aePC(32:2); aePC(34:0);        PC(44:2); SM(16:0); SM(18:0); SM(22:0); SM(24:0); SM(24:1);        aePC(36:5); aePC(38:5); aePC(40:5); 1PC(20:5); 1PC(22:5);        PC(36:5); PC(38:5); PC(40:5); PI(38:5); PI(40:5); C20:5 CE;        C22:6 CE; aePC(38:6); aePC(40:6); aePE(40:6); PC(36:6);        PC(38:6); PC(40:6); PC(42:6); PI(40:6); C22:5 CE; aePE(38:6);        1PE(22:6); PE(38:6); PE(40:6); PI(38:6); PC(40:7); PC(40:8);        PC(42:10); PC(42:7); PC(42:8); PC(42:9); PE(40:7); 1PC(22:6);        C19:0 CE; C19:1 CE; C20:0 CE; C20:1 CE; C20:3 CE; PE(34:1);        PE(34:2); PE(36:1); PE(36:2); PE(36:3); PE(36:4); PE(38:3);        PE(38:4); PE(40:4); PI(36:3); PI(38:3); PS(38:4); aePC(36:1);        aePC(38:1); aePC(38:2); aePC(38:3); aePC(40:2); aePC(40:3);        1PC(20:3); PC(34:3); PC(36:3); PC(38:1); PC(38:2); PC(40:3); and        PE(40:5);    -   b) selecting a subject having an impaired plasma level of one or        more of said plasma polar lipids;    -   c) administering to said selected subject a composition        comprising at least one, preferably at least two, most        preferably all B vitamins selected from the group consisting of        vitamin B6, vitamin B12 and vitamin B9, and optionally one or        more of uridine and cytidine, or salts, phosphates, acyl        derivatives or esters thereof.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the invention pertains to the use of a preparation forthe manufacture of a composition for treating (preferably amelioratingor normalizing) or preventing impaired plasma polar lipid levels,preferably phospholipid levels in a preclinical AD or MCI subject or asubject with a high likelihood of developing AD or MCI, wherein saidsubject is administered with a composition comprising at least one,preferably at least two, most preferably all B vitamins selected fromthe group consisting of vitamin B6, vitamin B12 and vitamin B9. Thecomposition preferably further comprises one or more of uridine andcytidine, or salts, phosphates, acyl derivatives or esters thereof.

In a second aspect, the invention pertains to a method for treating(preferably ameliorating or normalizing) or preventing impaired plasmapolar lipid levels, preferably phospholipid levels in a preclinical ADor MCI subject or a subject with a high likelihood of developing AD orMCI, comprising:

-   -   a) analyzing plasma levels of at least one phospholipid in a        subject;    -   b) selecting a subject having an impaired plasma phospholipid        level, preferably an impaired plasma phosphatidylcholine level,        preferably an impaired plasma level of one or more        phosphatidylcholine species selected from the group consisting        of phosphatidylcholine diacyl C36:6 [PC aa C36:6], PC aa C38:0,        PC aa C38:6, PC aa C40:6 and PC acyl-alkyl C40:6 [PC ae C40:6];    -   c) administering to said selected subject a composition        comprising at least one, preferably at least two, most        preferably all B vitamins selected from the group consisting of        vitamin B6, vitamin B12 and vitamin B9, and optionally one or        more of uridine and cytidine, or salts, phosphates, acyl        derivatives or esters thereof.

Treatment of impaired polar lipid levels preferably involvesameliorating or normalizing said levels. With ameliorating ornormalizing impaired phospholipid metabolism it is preferably understoodthat the (impaired) plasma levels of at least 1, preferably at least 2,more preferably at least 3 polar lipid levels, preferablyphosphatidylcholine species, even more preferably at least 4 polar lipidlevels, preferably phosphatidylcholine species monitored in said subjectduring intervention are changed significantly, preferably with at least2% more preferably at least 4%, even more preferably at least 6%,particularly at least 8%, especially at least 10%, more preferably atleast 15%, most preferably at least 20%, compared to the impaired levelsprior to intervention. Also, prevention of impaired plasma phospholipidlevels preferably means that plasma levels of the phospholipids aremaintained at normal range, preferably involving changes of less than20%, preferably less than 15%, preferably less than 10%, more preferablyless than 8%, even more preferably less than 5%, most preferably lessthan 5% of normal values. The prevention or treatment of impaired plasmalevels preferably concerns at least the polar lipid levels, preferablyPC species specifically mentioned in the application. The inventionparticularly relates to treatment of impaired plasma polar lipid levels.Abnormalities in these plasma polar lipid levels, preferably PC levelscan be assessed by either taking the average values for those plasmalevels determined correspondingly a healthy subject (of similar age) (somatched for e.g. age; not diagnosed with any neurological disorder orpreclinical AD or MCI) as a reference, and comparing the subject'scondition with the reference situation.

In a preferred embodiment, the treatment invokes an increase in thesepolar lipid levels, preferably PC levels, thus providing a solution toreduced plasma levels. The terminology ‘reduced plasma levels’ and‘depleted plasma levels’ are considered interchangeably, which arereadily assessed by skilled artisan.

In particular, in the context of the invention deficits or abnormalitiesin said plasma polar lipid species, preferably PC levels imply a changein plasma levels of preferably at least 2% change, more preferably atleast 4% change, even more preferably at least 6% change, particularlyat least 8% change, especially at least 10% change, more preferably atleast 15% change, most preferably at least 20% change, compared to thevalue as determined correspondingly in a healthy individual (of similarage). In one embodiment, the above change is preferably a decrease. Thevalue of x for the determination of those plasma levels is preferablychanged by at least 2% more preferably at least 4%, even more preferablyat least 6%, particularly at least 8%, especially at least 10%, morepreferably at least 15%, most preferably at least 20% when determinedunder standardized conditions in terms of feeding and exercise. In oneembodiment, the numbers preferably apply to a reduction.

In the context of the invention, polar lipids are defined as compoundsselected from the group of phosphatidylcholines,phosphatidylethanolamines, phosphatidylserines, phosphatidylinositols,plasmalogens, either substituted with acyl- and/or alkyl moieties,glycosylated lipids, glycosylated fatty acids, sphingolipids,sphingomyelins and cholesterylesters of fatty acids. The polar lipidsare preferably compounds selected from the group ofphosphatidylcholines, phosphatidylethanolamines, phosphatidylserines,phosphatidylinositols, most preferably PC compounds.

In one aspect, the invention is particularly directed to a specific setof polar lipid compounds, particularly phosphatidylcholine compounds. Ina preferred embodiment, the invention pertains to treating or preventingimpaired plasma levels of at least one, preferably at least two, morepreferably at least three polar lipid species, more preferablyphosphatidylcholine species selected from the group consisting ofphosphatidylcholine diacyl C36:6 [PC aa C36:6], phosphatidylcholinediacyl C38:0 [PC aa C38:0], phosphatidylcholine diacyl C38:6 [PC aaC38:6], phosphatidylcholine diacyl C40:6 [PC aa C40:6] andphosphatidylcholine acyl-alkyl C40:6 [PC ae C40:6]. The inventionparticularly relates to treating or preventing impaired plasma levels ofat least one polar lipid species, more preferably at least one PCspecies selected from the group consisting of 36:6, 38:6 and 40:6, morepreferably at least two of these polyunsaturated PC species. Theinvention is particularly directed to treating or preventing impairedplasma levels of at least PC aa 40:6 and/or PC ae 40:6, most preferablyat least PC aa 40:6.

In another aspect, the invention is particularly directed to a specificset of polar lipids selected from the group of phosphatidylcholines,phosphatidylethanolamines, phosphatidylserines, phosphatidylinositols,plasmalogens, either substituted with acyl- and/or alkyl moieties,glycosylated lipids, glycosylated fatty acids, sphingolipids,sphingomyelins and cholesterylesters of fatty acids. The polar lipidsare preferably compounds selected from the group ofphosphatidylcholines, phosphatidylethanolamines, phosphatidylserines,phosphatidylinositols.

Throughout the document, when addressing the preferred plasma polarlipids targeted with the invention,

PC=phospatidylcholine;PE=phosphatidylethanolamine;PI=phosphatidylinositol;PS=phosphatidylserine,CE=cholesterol ester;‘ae’ (as in aePC, aePS, aePE and aePl)=acyl-akyl;SM=sphingomyeline;DSM=dihydrosphingomyeline;‘1’ as in 1PC, 1PS, 1PE and 1PI)=lyso;PA=phosphatidic acid.

By way of example, ‘C16:1 CE’ stands for cholesterol ester with a carbonchain with 16 C atoms and 1 double or unsaturated bond.

In one embodiment, the polar lipids are selected from the groupconsisting of C16:1 CE; C18:3 CE; C20:4 CE; PI(34:1); PI(38:2);PI(38:4); C16:0 CE; C18:2 CE; PA(34:3); PE(36:0); PE(38:0); aePC(36:0);aePC(38:0); aePC(38:4); aePC(40:4); 1PC(18:0); 1PC(18:3); 1PC(20:4);PC(36:1); PC(38:0); PC(38:4); PC(40:4); DSM(18:0); aePC(32:1);aePC(32:2); aePC(34:0); PC(44:2); SM(16:0); SM(18:0); SM(22:0);SM(24:0); SM(24:1); aePC(36:5); aePC(38:5); aePC(40:5); 1PC(20:5);1PC(22:5); PC(36:5); PC(38:5); PC(40:5); PI(38:5); PI(40:5); C20:5 CE;C22:6 CE; aePC(38:6); aePC(40:6); aePE(40:6); PC(36:6); PC(38:6);PC(40:6); PC(42:6); PI(40:6); C22:5 CE; aePE(38:6); 1PE(22:6); PE(38:6);PE(40:6); PI(38:6); PC(40:7); PC(40:8); PC(42:10); PC(42:7); PC(42:8);PC(42:9); PE(40:7); and 1PC(22:6), for which it was found that plasmalevels could be increased with the composition according to theinvention, and polar lipids selected from the group consisting of C19:0CE; C19:1 CE; C20:0 CE; C20:1 CE; C20:3 CE; PE(34:1); PE(34:2);PE(36:1); PE(36:2); PE(36:3); PE(36:4); PE(38:3); PE(38:4); PE(40:4);PI(36:3); PI(38:3); PS(38:4); aePC(36:1); aePC(38:1); aePC(38:2);aePC(38:3); aePC(40:2); aePC(40:3); 1PC(20:3); PC(34:3); PC(36:3);PC(38:1); PC(38:2); PC(40:3); and PE(40:5), for which it was found thatplasma levels could be decreased with the composition according to theinvention.

More preferably, the plasma polar lipids which plasma levels areincreased by the composition according to the invention are selectedfrom the group consisting of C16:1 CE; C18:3 CE; C20:4 CE; PI(34:1);PI(38:2); PI(38:4); C16:0 CE; C18:2 CE; PA(34:3); PE(36:0); PE(38:0);aePC(36:0); aePC(38:0); aePC(38:4); aePC(40:4); 1PC(18:0); 1PC(18:3);1PC(20:4); PC(36:1); PC(38:0); PC(38:4); PC(40:4); DSM(18:0);aePC(32:1); aePC(32:2); aePC(34:0); PC(44:2); SM(16:0); SM(18:0);SM(22:0); SM(24:0); SM(24:1); aePC(36:5); aePC(38:5); aePC(40:5);1PC(20:5); 1PC(22:5); PC(36:5); PC(38:5); PC(40:5); PI(38:5); PI(40:5);C20:5 CE; C22:6 CE; aePC(38:6); aePC(40:6); aePE(40:6); PC(36:6);PC(38:6); PC(40:6); PC(42:6); PI(40:6); C22:5 CE; aePE(38:6); 1PE(22:6);PE(38:6); PE(40:6); PI(38:6); PC(40:7); PC(40:8); PC(42:10); PC(42:7);PC(42:8); PC(42:9); PE(40:7); and 1PC(22:6), more preferably selectedfrom the group consisting of PC(38:0); aePC(40:6); PC(36:6); PC(38:6);and PC(40:6).

In one embodiment, the polar lipids are selected from the groupconsisting of C16:1 CE; C18:3 CE; C20:4 CE; PI(34:1); PI(38:2);PI(38:4); C16:0 CE; C18:2 CE; PA(34:3); PE(36:0); PE(38:0); aePC(36:0);aePC(38:0); aePC(38:4); aePC(40:4); 1PC(18:0); 1PC(18:3); 1PC(20:4);PC(36:1); PC(38:0); PC(38:4); PC(40:4); DSM(18:0); aePC(32:1);aePC(32:2); aePC(34:0); PC(44:2); SM(16:0); SM(18:0); SM(22:0);SM(24:0); SM(24:1); aePC(36:5); aePC(38:5); aePC(40:5); 1PC(20:5);1PC(22:5); PC(36:5); PC(38:5); PC(40:5); PI(38:5); PI(40:5); C20:5 CE;C22:6 CE; aePC(38:6); aePC(40:6); aePE(40:6); PC(36:6); PC(38:6);PC(40:6); PC(42:6); PI(40:6); C22:5 CE; aePE(38:6); 1PE(22:6); PE(38:6);PE(40:6); PI(38:6); PC(40:7); PC(40:8); PC(42:10); PC(42:7); PC(42:8);PC(42:9); PE(40:7); and 1PC(22:6), for which it was found that plasmalevels could be increased with the composition according to theinvention, and polar lipids selected from the group consisting of C19:0CE; C19:1 CE; C20:0 CE; C20:1 CE; C20:3 CE; PE(34:1); PE(34:2);PE(36:1); PE(36:2); PE(36:3); PE(36:4); PE(38:3); PE(38:4); PE(40:4);PI(36:3); PI(38:3); PS(38:4); aePC(36:1); aePC(38:1); aePC(38:2);aePC(38:3); aePC(40:2); aePC(40:3); LPC(20:3); PC(34:3); PC(36:3);PC(38:1); PC(38:2); PC(40:3); and PE(40:5), for which it was found thatplasma levels could be decreased with the composition according to theinvention.

More preferably, the plasma polar lipids which are increased by thecomposition according to the invention are selected from the groupconsisting of C16:1 CE; C18:3 CE; C20:4 CE; PI(34:1); PI(38:2);PI(38:4); C16:0 CE; C18:2 CE; PA(34:3); PE(36:0); PE(38:0); aePC(36:0);aePC(38:0); aePC(38:4); aePC(40:4); 1PC(18:0); 1PC(18:3); 1PC(20:4);PC(36:1); PC(38:4); PC(40:4); DSM(18:0); aePC(32:1); aePC(32:2);aePC(34:0); PC(44:2); SM(16:0); SM(18:0); SM(22:0); SM(24:0); SM(24:1);aePC(36:5); aePC(38:5); aePC(40:5); 1PC(20:5); 1PC(22:5); PC(36:5);PC(38:5); PC(40:5); PI(38:5); PI(40:5); C20:5 CE; C22:6 CE; aePC(38:6);aePE(40:6); PC(42:6); PI(40:6); C22:5 CE; aePE(38:6); 1PE(22:6);PE(38:6); PE(40:6); PI(38:6); PC(40:7); PC(40:8); PC(42:10); PC(42:7);PC(42:8); PC(42:9); PE(40:7); and 1PC(22:6), and the plasma polar lipidswhich plasma levels are decreased by the composition according to theinvention are selected from the group consisting of C19:0 CE; C19:1 CE;C20:0 CE; C20:1 CE; C20:3 CE; PE(34:1); PE(34:2); PE(36:1); PE(36:2);PE(36:3); PE(36:4); PE(38:3); PE(38:4); PE(40:4); PI(36:3); PI(38:3);PS(38:4); aePC(36:1); aePC(38:1); aePC(38:2); aePC(38:3); aePC(40:2);aePC(40:3); LPC(20:3); PC(34:3); PC(36:3); PC(38:1); PC(38:2); PC(40:3);and PE(40:5).

Most preferably, the plasma polar lipids which are increased by thecomposition according to the invention are selected from the groupconsisting of 1PC(18:0); 1PC(20:5); 1PC(22:6); PC(36:5); PC(38:4);PC(38:5); PE(38:6); PE(40:6); PE(40:7); aePC(38:5); aePC(38:6); andaePE(38:6) and the plasma polar lipids which plasma levels are decreasedby the composition according to the invention are preferably PC(34:3)and/or PC(36:3).

In one embodiment, the polar lipids are selected from the groupconsisting of C16:1 CE; C18:3 CE; C20:4 CE; PI(34:1); PI(38:2);PI(38:4); C16:0 CE; C18:2 CE; PA(34:3); PE(36:0); PE(38:0); aePC(36:0);aePC(38:0); aePC(38:4); aePC(40:4); 1PC(18:0); 1PC(18:3); 1PC(20:4);PC(36:1); PC(38:0); PC(38:4); PC(40:4); DSM(18:0); aePC(32:1);aePC(32:2); aePC(34:0); PC(44:2); SM(16:0); SM(18:0); SM(22:0);SM(24:0); SM(24:1); aePC(36:5); aePC(38:5); aePC(40:5); 1PC(20:5);1PC(22:5); PC(36:5); PC(38:5); PC(40:5); PI(38:5); PI(40:5); C20:5 CE;C22:6 CE; aePC(38:6); aePC(40:6); aePE(40:6); PC(36:6); PC(38:6);PC(40:6); PC(42:6); PI(40:6); C22:5 CE; aePE(38:6); 1PE(22:6); PE(38:6);PE(40:6); PI(38:6); PC(40:7); PC(40:8); PC(42:10); PC(42:7); PC(42:8);PC(42:9); PE(40:7); and 1PC(22:6), for which it was found that plasmalevels could be increased with the composition according to theinvention, and polar lipids selected from the group consisting of C19:0CE; C19:1 CE; C20:0 CE; C20:1 CE; C20:3 CE; PE(34:1); PE(34:2);PE(36:1); PE(36:2); PE(36:3); PE(36:4); PE(38:3); PE(38:4); PE(40:4);PI(36:3); PI(38:3); PS(38:4); aePC(36:1); aePC(38:1); aePC(38:2);aePC(38:3); aePC(40:2); aePC(40:3); 1PC(20:3); PC(34:3); PC(36:3);PC(38:1); PC(38:2); PC(40:3); and PE(40:5).

More preferably, the plasma polar lipids which plasma levels areincreased by the composition according to the invention are selectedfrom the group consisting of C16:1 CE; C18:3 CE; C20:4 CE; PI(34:1);PI(38:2); PI(38:4); C16:0 CE; C18:2 CE; PA(34:3); PE(36:0); PE(38:0);aePC(36:0); aePC(38:0); aePC(38:4); aePC(40:4); 1PC(18:0); 1PC(18:3);1PC(20:4); PC(36:1); PC(38:0); PC(38:4); PC(40:4); DSM(18:0);aePC(32:1); aePC(32:2); aePC(34:0); PC(44:2); SM(16:0); SM(18:0);SM(22:0); SM(24:0); SM(24:1); aePC(36:5); aePC(38:5); aePC(40:5);1PC(20:5); 1PC(22:5); PC(36:5); PC(38:5); PC(40:5); PI(38:5); PI(40:5);C20:5 CE; C22:6 CE; aePC(38:6); aePC(40:6); aePE(40:6); PC(36:6);PC(38:6); PC(40:6); PC(42:6); PI(40:6); C22:5 CE; aePE(38:6); 1PE(22:6);PE(38:6); PE(40:6); PI(38:6); PC(40:7); PC(40:8); PC(42:10); PC(42:7);PC(42:8); PC(42:9); PE(40:7); and 1PC(22:6),

Most preferably, the plasma polar lipids which plasma levels areincreased by the composition according to the invention are selectedfrom the group consisting of PC(36:5); C(38:6); PC(40:6), particularlyPC(36:5).

In one embodiment, the polar lipids are selected from the groupconsisting of C16:1 CE; C18:3 CE; C20:4 CE; PI(34:1); PI(38:2);PI(38:4); C16:0 CE; C18:2 CE; PA(34:3); PE(36:0); PE(38:0); aePC(36:0);aePC(38:0); aePC(38:4); aePC(40:4); 1PC(18:0); 1PC(18:3); 1PC(20:4);PC(36:1); PC(38:0); PC(38:4); PC(40:4); DSM(18:0); aePC(32:1);aePC(32:2); aePC(34:0); PC(44:2); SM(16:0); SM(18:0); SM(22:0);SM(24:0); SM(24:1); aePC(36:5); aePC(38:5); aePC(40:5); 1PC(20:5);1PC(22:5); PC(36:5); PC(38:5); PC(40:5); PI(38:5); PI(40:5); C20:5 CE;C22:6 CE; aePC(38:6); aePC(40:6); aePE(40:6); PC(36:6); PC(38:6);PC(40:6); PC(42:6); PI(40:6); C22:5 CE; aePE(38:6); 1PE(22:6); PE(38:6);PE(40:6); PI(38:6); PC(40:7); PC(40:8); PC(42:10); PC(42:7); PC(42:8);PC(42:9); PE(40:7); and 1PC(22:6), for which it was found that plasmalevels could be increased with the composition according to theinvention, and polar lipids selected from the group consisting of C19:0CE; C19:1 CE; C20:0 CE; C20:1 CE; C20:3 CE; PE(34:1); PE(34:2);PE(36:1); PE(36:2); PE(36:3); PE(36:4); PE(38:3); PE(38:4); PE(40:4);PI(36:3); PI(38:3); PS(38:4); aePC(36:1); aePC(38:1); aePC(38:2);aePC(38:3); aePC(40:2); aePC(40:3); 1PC(20:3); PC(34:3); PC(36:3);PC(38:1); PC(38:2); PC(40:3); and PE(40:5), for which it was found thatplasma levels could be decreased with the composition according to theinvention.

More preferably, the plasma polar lipids which plasma levels areincreased by the composition according to the invention are selectedfrom the group consisting of C16:1 CE; C18:3 CE; C20:4 CE; PI(34:1);PI(38:2); PI(38:4); C16:0 CE; C18:2 CE; PA(34:3); PE(36:0); PE(38:0);aePC(36:0); aePC(38:0); aePC(38:4); aePC(40:4); 1PC(18:0); 1PC(18:3);1PC(20:4); PC(36:1); PC(38:0); PC(38:4); PC(40:4); DSM(18:0);aePC(32:1); aePC(32:2); aePC(34:0); PC(44:2); SM(16:0); SM(18:0);SM(22:0); SM(24:0); SM(24:1); aePC(36:5); aePC(38:5); aePC(40:5);1PC(20:5); 1PC(22:5); PC(36:5); PC(38:5); PC(40:5); PI(38:5); PI(40:5);C20:5 CE; C22:6 CE; aePC(38:6); aePC(40:6); aePE(40:6); PC(36:6);PC(38:6); PC(40:6); PC(42:6); PI(40:6); C22:5 CE; aePE(38:6); 1PE(22:6);PE(38:6); PE(40:6); PI(38:6); PC(40:7); PC(40:8); PC(42:10); PC(42:7);PC(42:8); PC(42:9); PE(40:7); and LPC(22:6).

Most preferably, the plasma polar lipids which are increased by thecomposition according to the invention are selected from the groupconsisting of C16:1 CE; C18:3 CE; C20:4 CE; PI(34:1); PI(38:2);PI(38:4); C16:0 CE; C18:2 CE; PA(34:3); PE(36:0); PE(38:0); aePC(36:0);aePC(38:0); aePC(38:4); aePC(40:4); 1PC(18:0); 1PC(18:3); 1PC(20:4);PC(36:1); PC(38:4); PC(40:4); DSM(18:0); aePC(32:1); aePC(32:2);aePC(34:0); PC(44:2); SM(16:0); SM(18:0); SM(22:0); SM(24:0); SM(24:1);aePC(36:5); aePC(38:5); aePC(40:5); 1PC(20:5); 1PC(22:5); PC(36:5);PC(38:5); PC(40:5); PI(38:5); PI(40:5); C20:5 CE; C22:6 CE; aePC(38:6);aePE(40:6); PC(42:6); PI(40:6); C22:5 CE; aePE(38:6); 1PE(22:6);PE(38:6); PE(40:6); PI(38:6); PC(40:7); PC(40:8); PC(42:10); PC(42:7);PC(42:8); PC(42:9); PE(40:7); and 1PC(22:6), particularly PC(38:4);PI(38:4); SM(24:1).

In one embodiment, the plasma polar lipids which plasma levels areincreased by the composition according to the invention are selectedfrom the group consisting of C16:1 CE; C18:3 CE; C20:4 CE; PI(34:1);PI(38:2); PI(38:4); C16:0 CE; C18:2 CE; PA(34:3); PE(36:0); PE(38:0);aePC(36:0); aePC(38:0); aePC(38:4); aePC(40:4); 1PC(18:0); 1PC(18:3);1PC(20:4); PC(36:1); PC(38:0); PC(38:4); PC(40:4); DSM(18:0);aePC(32:1); aePC(32:2); aePC(34:0); PC(44:2); SM(16:0); SM(18:0);SM(22:0); SM(24:0); SM(24:1); aePC(36:5); aePC(38:5); aePC(40:5);1PC(20:5); 1PC(22:5); PC(36:5); PC(38:5); PC(40:5); PI(38:5); PI(40:5);C20:5 CE; C22:6 CE; aePC(38:6); aePC(40:6); aePE(40:6); PC(36:6);PC(38:6); PC(40:6); PC(42:6); PI(40:6); C22:5 CE; aePE(38:6); 1PE(22:6);PE(38:6); PE(40:6); PI(38:6); PC(40:7); PC(40:8); PC(42:10); PC(42:7);PC(42:8); PC(42:9); PE(40:7); and 1PC(22:6).

More preferably, the polar lipid contains choline and/or has more than 4double bonds, and is selected from the group consisting of aePC(36:0);aePC(38:0); aePC(38:4); aePC(40:4); LPC(18:0); LPC(18:3); LPC(20:4);PC(36:1); PC(38:0); PC(38:4); PC(40:4); DSM(18:0); aePC(32:1);aePC(32:2); aePC(34:0); PC(44:2); SM(16:0); SM(18:0); SM(22:0);SM(24:0); SM(24:1); aePC(36:5); aePC(38:5); aePC(40:5); 1PC(20:5);1PC(22:5); PC(36:5); PC(38:5); PC(40:5); PI(38:5); PI(40:5); C20:5 CE;C22:6 CE; aePC(38:6); aePC(40:6); aePE(40:6); PC(36:6); PC(38:6);PC(40:6); PC(42:6); PI(40:6); C22:5 CE; aePE(38:6); 1PE(22:6); PE(38:6);PE(40:6); PI(38:6); PC(40:7); PC(40:8); PC(42:10); PC(42:7); PC(42:8);PC(42:9); PE(40:7); and 1PC(22:6).

More preferably, the polar lipid has more than 4 double bonds, and isselected from the group consisting of aePC(36:5); aePC(38:5);aePC(40:5); 1PC(20:5); 1PC(22:5); PC(36:5); PC(38:5); PC(40:5);PI(38:5); PI(40:5); C20:5 CE; C22:6 CE; aePC(38:6); aePC(40:6);aePE(40:6); PC(36:6); PC(38:6); PC(40:6); PC(42:6); PI(40:6); C22:5 CE;aePE(38:6); 1PE(22:6); PE(38:6); PE(40:6); PI(38:6); PC(40:7); PC(40:8);PC(42:10); PC(42:7); PC(42:8); PC(42:9); PE(40:7); LPC(22:6), morepreferably the polar lipid has more than 5 double bonds, and is selectedfrom the group consisting of C22:6 CE; aePC(38:6); aePC(40:6);aePE(40:6); PC(36:6); PC(38:6); PC(40:6); PC(42:6); PI(40:6); C22:5 CE;aePE(38:6); 1PE(22:6); PE(38:6); PE(40:6); PI(38:6); PC(40:7); PC(40:8);PC(42:10); PC(42:7); PC(42:8); PC(42:9); PE(40:7); 1PC(22:6), even morepreferably the polar lipid has more than 6 double bonds, and is selectedfrom the group consisting of PC(40:7); PC(40:8); PC(42:10); PC(42:7);PC(42:8); PC(42:9); PE(40:7); and LPC(22:6), particularly 1PC(22:6).

In one embodiment, the plasma polar lipids which are increased by thecomposition according to the invention are selected from the groupconsisting of C16:1 CE; C18:3 CE; C20:4 CE; PI(34:1); PI(38:2);PI(38:4); C16:0 CE; C18:2 CE; PA(34:3); PE(36:0); PE(38:0); aePC(36:0);aePC(38:0); aePC(38:4); aePC(40:4); 1PC(18:0); 1PC(18:3); 1PC(20:4);PC(36:1); PC(38:4); PC(40:4); DSM(18:0); aePC(32:1); aePC(32:2);aePC(34:0); PC(44:2); SM(16:0); SM(18:0); SM(22:0); SM(24:0); SM(24:1);ePC(36:5); ePC(38:5); aePC(40:5); 1PC(20:5); 1PC(22:5); PC(36:5);PC(38:5); PC(40:5); PI(38:5); PI(40:5); C20:5 CE; C22:6 CE; aePC(38:6);aePE(40:6); PC(42:6); PI(40:6); C22:5 CE; aePE(38:6); 1PE(22:6);PE(38:6); PE(40:6); PI(38:6); PC(40:7); PC(40:8); PC(42:10); PC(42:7);PC(42:8); PC(42:9); PE(40:7); 1PC(22:6).

More preferably, the polar lipid contains choline and/or has more than 4double bonds, and is selected from the group consisting of aePC(36:0);aePC(38:0);

aePC(38:4); aePC(40:4); 1PC(18:0); 1PC(18:3); 1PC(20:4); PC(36:1);PC(38:4); PC(40:4); DSM(18:0); aePC(32:1); aePC(32:2); aePC(34:0);PC(44:2); SM(16:0); SM(18:0); SM(22:0); SM(24:0); SM(24:1); aePC(36:5);aePC(38:5); aePC(40:5); 1PC(20:5); 1PC(22:5); PC(36:5); PC(38:5);PC(40:5); PI(38:5); PI(40:5); C20:5 CE; C22:6 CE; ePC(38:6); ePE(40:6);PC(42:6); PI(40:6); C22:5 CE; aePE(38:6); 1PE(22:6); PE(38:6); PE(40:6);PI(38:6); PC(40:7); PC(40:8); PC(42:10); PC(42:7); PC(42:8); PC(42:9);PE(40:7); LPC(22:6).

More preferably, the polar lipid has more than 4 double bonds, and isselected from the group consisting of aePC(36:5); aePC(38:5);aePC(40:5); 1PC(20:5); 1PC(22:5); PC(36:5); PC(38:5); PC(40:5);PI(38:5); PI(40:5); C20:5 CE; C22:6 CE; aePC(38:6); aePE(40:6);PC(42:6); PI(40:6); C22:5 CE; aePE(38:6); 1PE(22:6); PE(38:6); PE(40:6);PI(38:6); PC(40:7); PC(40:8); PC(42:10); PC(42:7); PC(42:8); PC(42:9);PE(40:7); 1PC(22:6), even more preferably the polar lipid has more than6 double bonds, and is selected from the group consisting of C22:6 CE;aePC(38:6); aePE(40:6); PC(42:6); PI(40:6); C22:5 CE; aePE(38:6);1PE(22:6); PE(38:6); PE(40:6); PI(38:6); PC(40:7); PC(40:8); PC(42:10);PC(42:7); PC(42:8); PC(42:9); PE(40:7); 1PC(22:6), particularly1PC(22:6).

In one embodiment, the polar lipids are selected from the groupconsisting of C19:0 CE; C19:1 CE; C20:0 CE; C20:1 CE; C20:3 CE;PE(34:1); PE(34:2); PE(36:1); PE(36:2); PE(36:3); PE(36:4); PE(38:3);PE(38:4); PE(40:4); PI(36:3); PI(38:3); PS(38:4); aePC(36:1);aePC(38:1); aePC(38:2); aePC(38:3); aePC(40:2); aePC(40:3); 1PC(20:3);PC(34:3); PC(36:3); PC(38:1); PC(38:2); PC(40:3); PE(40:5), for which itwas found that plasma levels could be decreased with the compositionaccording to the invention.

More preferably, the plasma polar lipids which are decreased by thecomposition according to the invention contain choline and/or more than4 double bonds and are selected from the group consisting of aePC(36:1);aePC(38:1); aePC(38:2); aePC(38:3); aePC(40:2); aePC(40:3); 1PC(20:3);PC(34:3); PC(36:3); PC(38:1); PC(38:2); PC(40:3); PE(40:5), particularlythe plasma polar lipid with more than 4 double bounds PE(40:5).

In one embodiment, the plasma polar lipids have more than 3 double bondsand are selected from the group consisting of C22:5 CE; 1PC(22:5); C20:4CE; aePC(38:4); aePC(40:4); 1PC(20:4); PC(38:4); PI(38:4); PC(40:4);C20:5 CE; aePC(36:5); aePC(40:5); 1PC(20:5); PC(36:5); PC(36:6);PC(38:5); PI(40:5); ePC(38:5); PC(40:5); PI(38:5); PC(42:8); PC(42:6);PC(40:8); PC(42:10); PC(42:7); PC(42:9); C22:6 CE; aePC(38:6);aePC(40:6); aePE(38:6); aePE(40:6); 1PE(22:6); PC(38:6); PC(40:6);PC(40:7); PE(38:6); PE(40:6); PE(40:7); PI(38:6); PI(40:6); 1PC(22:6),for which it was found that plasma levels could be increased with thecomposition according to the invention, and polar lipids having morethan 3 double bonds.

More preferably, the plasma polar lipids having more than 3 doublebonds, which plasma polar lipids are increased by the compositionaccording to the invention are selected from the group consisting ofC22:5 CE; 1PC(22:5); C20:4 CE; aePC(38:4); aePC(40:4); 1PC(20:4);PC(38:4); PI(38:4); PC(40:4); C20:5 CE; aePC(36:5); aePC(40:5);1PC(20:5); PC(36:5); PC(38:5); PI(40:5); aePC(38:5); PC(40:5); PI(38:5);PC(42:8); PC(42:6); PC(40:8); PC(42:10); PC(42:7); PC(42:9); C22:6 CE;aePC(38:6); aePE(38:6); aePE(40:6); LPE(22:6); PC(40:7); PE(38:6);PE(40:6); PE(40:7); PI(38:6); PI(40:6); 1PC(22:6).

In one embodiment, the plasma polar lipids have more than 3 doublebonds, contain DHA, EPA or AA and which plasma polar lipids areincreased by the composition according to the invention are selectedfrom the group consisting of C20:4 CE; aePC(38:4); aePC(40:4);1PC(20:4); PC(38:4); PI(38:4); PC(40:4); C20:5 CE; aePC(36:5);aePC(40:5); 1PC(20:5); PC(36:5); PC(36:6); PC(38:5); PI(40:5);aePC(38:5); PC(40:5); PI(38:5); PC(42:8); PC(42:6); PC(40:8); PC(42:10);PC(42:7); PC(42:9); C22:6 CE; aePC(38:6); aePC(40:6); aePE(38:6);aePE(40:6); 1PE(22:6); PC(38:6); PC(40:6); PC(40:7); PE(38:6); PE(40:6);PE(40:7); PI(38:6); PI(40:6); 1PC(22:6), preferably selected from thegroup consisting of C20:4 CE; aePC(38:4); aePC(40:4); 1PC(20:4);PC(38:4); PI(38:4); PC(40:4); C20:5 CE; aePC(36:5); aePC(40:5);1PC(20:5); PC(36:5); PC(38:5); PI(40:5); aePC(38:5); PC(40:5); PI(38:5);PC(42:8); PC(42:6); PC(40:8); PC(42:10); PC(42:7); PC(42:9); C22:6 CE;aePC(38:6); aePE(38:6); aePE(40:6); LPE(22:6); PC(40:7); PE(38:6);PE(40:6); PE(40:7); PI(38:6); PI(40:6); 1PC(22:6), more preferablyselected from the group consisting of C20:5 CE; aePC(36:5); aePC(40:5);1PC(20:5); PC(36:5); PC(36:6); PC(38:5); PI(40:5); aePC(38:5); PC(40:5);PI(38:5); PC(42:8); PC(42:6); PC(40:8); PC(42:10); PC(42:7); PC(42:9);C22:6 CE; aePC(38:6); aePC(40:6); aePE(38:6); aePE(40:6); 1PE(22:6);PC(38:6); PC(40:6); PC(40:7); PE(38:6); PE(40:6); PE(40:7); PI(38:6);PI(40:6); 1PC(22:6), most preferably selected from the group consistingof C20:5 CE; aePC(36:5); aePC(40:5); 1PC(20:5); PC(36:5); PC(38:5);PI(40:5); aePC(38:5); PC(40:5); PI(38:5); PC(42:8); PC(42:6); PC(40:8);PC(42:10); PC(42:7); PC(42:9); C22:6 CE; aePC(38:6); aePE(38:6);aePE(40:6); 1PE(22:6); PC(40:7); PE(38:6); PE(40:6); PE(40:7); PI(38:6);PI(40:6); 1PC(22:6), particularly 1PC(22:6) and/or PC(40:6), especially1PC(22:6).

Alternatively, the plasma polar lipids be selected for having more than3 double bonds, not containing DHA, and which plasma polar lipid levelsare decreased by the composition according to the invention, in whichcase the polar lipid is preferably selected from the group consisting ofthe group consisting of PE(36:4); PE(38:4); PE(40:4); PS(38:4); andPE(40:5).

In one embodiment, the plasma polar lipids have more than 24 C atoms andare selected from the group consisting of aePC(32:1); aePC(32:2);aePC(34:0); PA(34:3); PI(34:1); aePC(36:5); aePC(38:0); aePC(38:4);aePC(38:6); aePE(38:6); PC(36:5); PC(36:6); PC(38:0); PC(38:4);PC(38:5); PC(38:6); PE(36:0); PE(38:0); PE(38:6); PI(38:6); aePC(36:0);aePC(38:5); PC(36:1); PI(38:2); PI(38:4); PI(38:5); aePC(40:4);aePC(40:5); aePC(40:6); aePE(40:6); PC(40:6); PC(40:7); PC(42:8);PC(44:2); PE(40:6); PE(40:7); PI(40:5); PI(40:6); PC(40:4); PC(40:5);PC(40:8); PC(42:10); PC(42:6); PC(42:7); PC(42:9), which plasma polarlipid levels are increased by the composition according to theinvention, and/or the plasma polar lipid has more than 24 C atoms and isselected from the group consisting of PC(34:3); PE(34:1); PE(34:2);aePC(36:1); aePC(38:1); aePC(38:2); aePC(38:3); PC(36:3); PC(38:1);PC(38:2); PE(36:1); PE(36:2); PE(36:3); PE(36:4); PE(38:3); PE(38:4);PI(36:3); PI(38:3); PS(38:4); aePC(40:2); aePC(40:3); PC(40:3);PE(40:4); PE(40:5) which plasma polar lipid levels are increased by thecomposition according to the invention.

Within the above groups, the preferred plasma polar lipids areaePC(32:1); aePC(32:2); aePC(34:0); PA(34:3); PI(34:1); aePC(36:5);aePC(38:0); aePC(38:4); aePC(38:6); aePE(38:6); PC(36:5); PC(38:4);PC(38:5); PE(36:0); PE(38:0); PE(38:6); PI(38:6); aePC(36:0);aePC(38:5); PC(36:1); PI(38:2); PI(38:4); PI(38:5); aePC(40:4);aePC(40:5); aePE(40:6); PC(40:7); PC(42:8); PC(44:2); PE(40:6);PE(40:7); PI(40:5); PI(40:6); PC(40:4); PC(40:5); PC(40:8); PC(42:10);PC(42:6); PC(42:7); PC(42:9), and PC(34:3); PE(34:1); PE(34:2);aePC(36:1); aePC(38:1); aePC(38:2); aePC(38:3); PC(36:3); PC(38:1);PC(38:2); PE(36:1); PE(36:2); PE(36:3); PE(36:4); PE(38:3); PE(38:4);PI(36:3); PI(38:3); PS(38:4); aePC(40:2); aePC(40:3); PC(40:3);PE(40:4); PE(40:5).

Within the above groups, even more preferred are aePC(36:5); aePC(38:0);aePC(38:4); aePC(38:6); aePE(38:6); PC(36:5); PC(36:6); PC(38:0);PC(38:4); PC(38:5); PC(38:6); PE(36:0); PE(38:0); PE(38:6); PI(38:6);aePC(36:0); aePC(38:5); PC(36:1); PI(38:2); PI(38:4); PI(38:5);aePC(40:4); aePC(40:5); aePC(40:6); aePE(40:6); PC(40:6); PC(40:7);PC(42:8); PC(44:2); PE(40:6); PE(40:7); PI(40:5); PI(40:6); PC(40:4);PC(40:5); PC(40:8); PC(42:10); PC(42:6); PC(42:7); PC(42:9), andaePC(36:1); aePC(38:1); aePC(38:2); aePC(38:3); PC(36:3); PC(38:1);PC(38:2); PE(36:1); PE(36:2); PE(36:3); PE(36:4); PE(38:3); PE(38:4);PI(36:3); PI(38:3); PS(38:4); aePC(40:2); aePC(40:3); PC(40:3);PE(40:4); PE(40:5)

Particularly preferred are aePC(36:5); aePC(38:0); aePC(38:4);aePC(38:6); aePE(38:6); PC(36:5); PC(38:4); PC(38:5); PE(36:0);PE(38:0); PE(38:6); PI(38:6); aePC(36:0); aePC(38:5); PC(36:1);PI(38:2); PI(38:4); PI(38:5); aePC(40:4); aePC(40:5); aePE(40:6);PC(40:7); PC(42:8); PC(44:2); PE(40:6); PE(40:7); PI(40:5); PI(40:6);PC(40:4); PC(40:5); PC(40:8); PC(42:10); PC(42:6); PC(42:7); PC(42:9),and aePC(36:1); aePC(38:1); aePC(38:2); aePC(38:3); PC(36:3); PC(38:1);PC(38:2); PE(36:1); PE(36:2); PE(36:3); PE(36:4); PE(38:3); PE(38:4);PI(36:3); PI(38:3); PS(38:4); aePC(40:2); aePC(40:3); PC(40:3);PE(40:4); PE(40:5).

Most preferred are those specific polar lipids having more than 38 Catoms, selected from the group consisting of aePC(40:4); aePC(40:5);aePC(40:6); aePE(40:6); PC(40:6); PC(40:7); PC(42:8); PC(44:2);PE(40:6); PE(40:7); PI(40:5); PI(40:6); PC(40:4); PC(40:5); PC(40:8);PC(42:10); PC(42:6); PC(42:7); PC(42:9), and aePC(40:2); aePC(40:3);PC(40:3); PE(40:4); PE(40:5) preferably aePC(40:4); aePC(40:5);aePE(40:6); PC(40:7); PC(42:8); PC(44:2); PE(40:6); PE(40:7); PI(40:5);PI(40:6).

Especially preferred are PC(40:4); PC(40:5); PC(40:8); PC(42:10);PC(42:6); PC(42:7); PC(42:9) [which plasma levels increase uponintervention with the composition of the invention] and aePC(40:2);aePC(40:3); PC(40:3); PE(40:4); PE(40:5) [which plasma levels increaseupon intervention with the composition of the invention].

In one embodiment, the plasma polar lipid contains choline, and isselected from the group consisting of DSM(18:0); aePC(32:1); aePC(32:2);aePC(34:0); aePC(36:5); aePC(38:0); aePC(38:4); aePC(38:6); aePC(40:4);aePC(40:5); aePC(40:6); LPC(18:3); LPC(20:4); LPC(20:5); LPC(22:6);PC(36:5); PC(36:6); PC(38:0); PC(38:4); PC(38:5); PC(38:6); PC(40:6);PC(40:7); PC(42:8); PC(44:2); SM(16:0); SM(18:0); SM(22:0); SM(24:0);SM(24:1); aePC(36:0); aePC(38:5); LPC(18:0); LPC(22:5); PC(36:1);PC(40:4); PC(40:5); PC(40:8); PC(42:10); PC(42:6); PC(42:7); PC(42:9)preferably DSM(18:0); aePC(32:1); aePC(32:2); aePC(34:0); aePC(36:5);aePC(38:0); aePC(38:4); aePC(38:6); aePC(40:4); aePC(40:5); LPC(18:3);LPC(20:4); LPC(20:5); LPC(22:6); PC(36:5); PC(38:4); PC(38:5); PC(40:7);PC(42:8); PC(44:2); SM(16:0); SM(18:0); SM(22:0); SM(24:0); SM(24:1);aePC(36:0); aePC(38:5); LPC(18:0); LPC(22:5); PC(36:1); PC(40:4);PC(40:5); PC(40:8); PC(42:10); PC(42:6); PC(42:7); PC(42:9). The plasmalevels of these choline-containing polar lipids increase uponintervention with the composition of the invention.

In one aspect, the most preferred plasma polar lipids are 1PC 22:6and/or PC 40:6, preferably at least 1PC 22:6.

In the method or use according to the invention, the B vitamins areadministered in therapeutically effective amounts to improve the plasmapolar lipid levels.

Subject

In particular, the subject is a human being that suffers from impairedplasma concentrations of at least one of the above species, whichsubject is at increased risk of developing preclinical AD or MCI, or isa preclinical AD or MCI subject.

The subject could be an adult, preferably elderly, not diagnosed withany cognitive or neurological disorder, which is preferably a subject inneed of an increase in the plasma concentration of the specific polarlipids mentioned here above. The subject in need thereof is preferablydefined as a subject of at least 50 years of age, male and/or female,the subject having a disturbed plasma polar lipid profile as definedearlier in the text. The subject can have preclinical MCI and/or AD, orthe subject can have a diagnosis of MCI and/or AD.

In one embodiment, a subject that may be targeted with the compositionof the invention suffers from impaired plasma polar lipidsconcentrations preferably impaired plasma phosphatidylcholineconcentrations compared to a control subject, preferably exhibitingplasma levels of at least 1, preferably at least 2, more preferably atleast 3 of said polar lipid species, preferably phosphatidylcholinespecies as defined above which are significantly changed, preferablywith at least 2% more preferably at least 4%, even more preferably atleast 6%, particularly at least 8%, especially at least 10%, morepreferably at least 15%, most preferably at least 20%. The plasmaphospholipids involve the specific polar lipid species, preferablyphosphatidylcholine species selected from the group consisting of PC aaC36:6, PC aa C38:0, PC aa C38:6, PC aa C40:6 and PC ae C40:6, morepreferably one or more PC species selected from the group consisting ofPC aa C36:6, PC aa C38:6, PC aa C40:6 and PC ae C40:6, most preferablyone or more PC species selected from the group consisting of PC aa C40:6and PC ae C40:6, most preferably at least PC aa 40:6.

In one embodiment, the polar lipid, preferably phosphatidylcholine, hasa glycerol portion and the glycerol portion is bonded to two fattyacids. The amount of carbons in the fatty acids is preferably about 16to 40 carbon atoms, preferably 16, 36, 38 or 40 carbon atoms, mostpreferably at least 36 carbon atoms. The fatty acids preferably haveabout 0-6 double bonds, preferably 1-6 double bonds, more preferably at2 double bonds.

The subject is preferably a human, preferably an elderly human being,‘elderly’ meaning preferably at least 50 years of age. Preferably theelderly subject has no cognitive deficits.

In one embodiment, the subject is preferably a drug-naïve subject, whichsubject has preferably not been administered any drug for memoryimprovement and or for AD at least 4 weeks prior to the administrationof a composition according to the invention. Preferably, the term ‘drugnaïve’ as used in the present invention refers to subjects who do notingest one or more of cholinesterase inhibitors, N-methyl-D-aspartate(NMDA) antagonists and ginkgo biloba during treatment with thecomposition of the invention, and preferably have not taken anycognitive ability-affecting drugs in the 4 weeks prior to the treatment.

Product

Throughout the application, the terms ‘product’ and ‘composition’ areused interchangeably and account for the combination of ingredientsadministered to a subject in need thereof.

In one aspect of the present invention, the composition according to theinvention may be used as a pharmaceutical product comprising one or morepharmaceutically acceptable carrier materials. In another, preferredaspect of the present invention, the composition according to theinvention may be used as a nutritional product, for example as anutritional supplement, e.g., as an additive to a normal diet, as afortifier, to add to a normal diet, or as a complete nutrition.

The pharmaceutical product, preferably for enteral application, may be asolid or liquid galenical formulation. Examples of solid galenicalformulations are tablets, capsules (e.g. hard or soft shell gelatinecapsules), pills, sachets, powders, granules and the like which containthe active ingredient together with conventional galenical carriers. Anyconventional carrier material can be utilized. The carrier material canbe organic or inorganic inert carrier material suitable for oraladministration. Suitable carriers include water, gelatine, gum Arabic,lactose, starch, magnesium stearate, talc, vegetable oils, and the like.Additionally, additives such as flavoring agents, preservatives,stabilizers, emulsifying agents, buffers and the like may be added inaccordance with accepted practices of pharmaceutical compounding. Whilethe individual active ingredients are suitably administered in a singlecomposition, they may also be administered in individual dosage units.If the composition is a pharmaceutical product, such product may containthe daily dosage in one or more dosage units. The dosage unit may be ina liquid form or in a solid form, wherein in the latter case the dailydosage may be provided by one or more solid dosage units, e.g. in one ormore capsules or tablets.

In another aspect of the present invention, the composition according tothe invention may be used in a nutritional product comprising at leastone component selected from the group of fats, proteins, andcarbohydrates. It is understood that a nutritional product differs froma pharmaceutical product by the presence of nutrients which providenutrition to the subject to which the composition is administered, inparticular the presence of protein, fat, digestible carbohydrates anddietary fibers. It may further contain ingredients such as minerals,vitamins, organic acids, and flavoring agents. Although the term“nutraceutical product” is often used in literature, it denotes anutritional product with a pharmaceutical component or pharmaceuticalpurpose. Hence, the nutritional composition according to the inventionmay also be used in a nutraceutical product.

The product according to the invention comprises at least one B complexvitamin, preferably a B vitamin selected from the group consisting ofvitamin B6 (pyridoxine, pyridoxal, or pyridoxamine, or pyridoxinehydrochloride), vitamin B9 (folic acid or folate), and vitamin B12(various cobalamins). Throughout the application, functional equivalentsare encompassed within these terms.

Preferably the present composition comprises at least two selected fromthe group consisting of vitamin B6, vitamin B12 and vitamin B9. Inparticular, good results have been achieved with a combinationcomprising vitamin B6 and vitamin B9. In one embodiment, the compositioncomprises vitamins B6, B9 and B12. Again, functional equivalents areencompassed within these terms.

The vitamin B is to be administered in an effective dose, which dosedepends on the type of vitamin B used. As a rule of thumb, a suitableminimum or a maximum dose may be chosen based on known dietaryrecommendations, for instance as recommended by Institute of Medicine(TOM) of the U.S. National Academy of Sciences or by ScientificCommittee on Food (a scientific committee of the EU), the informationdisclosed herein and optionally a limited amount of routine testing. Aminimum dose may be based on the estimated average requirement (EAR),although a lower dose may already be effective. A maximum dosepreferably does not exceed the tolerable upper intake levels (UL), asrecommended by IOM.

If present in the nutritional composition or medicament, the vitamin B6is preferably present in an amount to provide a daily dosage in therange of 0.5 to 100 mg, in particular in the range of 0.7 to 20 mg, morein particular in the range of 0.8 to 10 mg. The present compositionpreferably comprises 0.5 to 100 mg vitamin B6 per 100 g (liquid)product, more preferably 0.7 to 20 mg vitamin B6 per 100 g (liquid)product, more preferably 0.8 to 10 mg vitamin B6 per 100 g (liquid)product.

If present in the nutritional composition or medicament, the vitamin B12is preferably present in an amount to provide a daily dosage in therange of 0.5 to 10000 μg, more preferably 0.5 to 1000 μg, in particularin the range of 0.8 to 500 μg, more in particular in the range of 1 to 5μg. The present composition preferably comprises 0.5-10000 μg, morepreferably 0.5-1000 μg vitamin B12 per 100 g (liquid) product, morepreferably 0.8 to 500 μg vitamin B12 per 100 g (liquid) product, morepreferably 1 to 5 vitamin B12 per 100 g (liquid) product. The term“vitamin B12” incorporates all cobalbumin equivalents known in the art.

Throughout the application, the terms ‘folic acid’, ‘folate’ and ‘B9’are used interchangeably. If present in the nutritional composition ormedicament, the vitamin B9 is preferably present in an amount to providea daily dosage in the range of 100 to 5000 μg, in particular in therange of 150 to 1000 μg, more in particular in the range of 200 to 600μg. The present composition preferably comprises 100 to 5000 μg folicacid per 100 g (liquid) product, more preferably 150 to 1000 μg folicacid per 100 g (liquid) product, more preferably 200 to 600 μg folicacid per 100 g (liquid) product. Folates include folic acid, folinicacid, methylated, methenylated and formylated forms of folates, theirsalts or esters, as well as their derivatives with one or more glutamicacid, and all in either reduced or oxidized form.

The product of the invention is an enteral composition, intended fororal administration. It is preferably administered in liquid form. Inone embodiment, the product comprises a lipid fraction and at least oneof carbohydrates and proteins, wherein the lipid composition providesbetween 20 and 50 energy % of the food product. In one embodiment, thefood product is a liquid composition containing between 0.8 and 1.4 kcalper ml.

Preferably, the composition comprising B vitamin(s) further comprises anuridine source.

Uridine, UMP

The present composition preferably comprises uridine, cytidine and/or anequivalent thereof, including salts, phosphates, acyl derivatives and/oresters. In terms of uridine, the composition preferably comprises atleast one uridine or an equivalent thereof selected from the groupconsisting of uridine (i.e. ribosyl uracil), deoxyuridine (deoxyribosyluracil), uridine phosphates (UMP, dUMP, UDP, UTP), nucleobase uracil andacylated uridine derivatives. In one embodiment, cytidine, CMP,citicoline (CDP-choline) may also be applied. Preferably, thecomposition to be administered according to the present inventioncomprises a source of uridine selected from the group consisting ofuridine, deoxyuridine, uridine phosphates, uracil, and acylated uridine,and cytidine, more preferably selected from the group consisting ofuridine, deoxyuridine, uridine phosphates, uracil, and acylated uridine.

Preferably, the present composition comprises an uridine phosphateselected from the group consisting of uridine monophosphate (UMP),uridine diphosphate (UDP) and uridine triphosphate (UTP); and/or acytidine phosphate (CMP, CDP, CTP, preferably CMP). Most preferably thepresent composition comprises UMP, as UMP is most efficiently beingtaken up by the body. Preferably at least 50 weight % of the uridine inthe present composition is provided by UMP, more preferably at least 75weight %, most preferably at least 95 weight %. Doses that must beadministered are given as UMP. The amount of uracil sources can becalculated taking the molar equivalent to the UMP amount (molecularweight 324 Dalton).

The present method preferably comprises the administration of uridine(the cumulative amount of uridine, deoxyuridine, uridine phosphates,nucleobase uracil and acylated uridine derivatives) in an amount of inan amount of 0.08-3 g per day, preferably 0.1-2 g per day, morepreferably 0.2-1 g per day. The present method preferably comprises theadministration of a composition comprising uridine in an amount of0.08-3 g UMP per 100 ml liquid product, preferably 0.1-2 g UMP per 100ml liquid product, more preferably 0.2-1 g per 100 ml liquid product.Preferably 1-37.5 mg UMP per kilogram body weight is administered perday. The above amounts also account for any amounts of cytidine,cytidine phosphates and citicoline incorporated in the composition ormethod.

Preferably, the present composition comprises uridine phosphate,preferably uridine monophosphate (UMP). The UMP is very efficientlytaken up by the body. Hence, inclusion of UMP in the present compositionenables a high effectivity at the lowest dosage and/or theadministration of a low volume to the subject.

Choline

In a preferred embodiment, the present composition contains choline, acholine salt and/or choline ester. For the remainder of the paragraph,the term ‘choline’ shall be considered to encompass all theseequivalents. The choline salt is preferably selected from cholinechloride, choline bitartrate, or choline stearate. The choline ester ispreferably selected from a phosphatidylcholine andlyso-phosphatidylcholine. The present method preferably comprises theadministration of more than 50 mg choline per day, preferably 80 to 2000mg choline per day, more preferably 120 to 1000 mg choline per day, mostpreferably 150 to 600 mg choline per day. The present compositionpreferably comprises 50 mg to 3000 gram choline per 100 ml of the liquidcomposition, preferably 200 mg to 1000 mg choline per 100 ml. The abovenumbers are based on choline, the amounts of choline equivalents orsources can be calculated taking the molar equivalent to choline intoaccount.

DHA/EPA

In one embodiment, the composition preferably further comprises, inaddition to the B vitamin component(s) and the preferred uridinecompound(s), a lipid fraction comprising at least one of docosahexaenoicacid (22:6; DHA), eicosapentaenoic acid (20:5; EPA) and docosapentaenoicacid (22:5; DPA), or esters thereof. In the context of the invention,‘DPA’ is understood to comprise the omega-3 (22:5) DPA only.

The composition preferably comprises at least one ω-3 polyunsaturatedfatty acid (LC PUFA; having a chain length of 18 and more carbon atoms)selected from the group consisting of docosahexaenoic acid (22:6; DHA),eicosapentaenoic acid (20:5; EPA) and docosapentaenoic acid (22:5 ω-3;DPA), preferably at least one of DHA and EPA. Preferably the presentcomposition contains at least DHA, more preferably DHA and EPA. EPA isconverted to DPA (ω-3), increasing subsequent conversion of DPA to DHAin the brain. Hence, the present composition preferably contains asignificant amount of EPA, so to further stimulate in vivo DHAformation.

The DHA, EPA and/or DPA are preferably provided as triglycerides,diglycerides, monoglycerides, free fatty acids or their salts or esters,phospholipids, lysophospholipids, glycerol ethers, lipoproteins,ceramides, glycolipids or combinations thereof. Preferably, the presentcomposition comprises at least DHA in triglyceride form.

In terms of daily dosage, the present method preferably comprises theadministration of 400 to 5000 mg DHA+EPA+DPA (preferably DHA+EPA) perday, more preferably 500 to 3000 mg (preferably DHA+EPA) per day, mostpreferably 1000 to 2500 mg (preferably DHA+EPA) per day. DHA ispreferably administered in an amount of 300 to 4000 mg per day, morepreferably 500 to 2500 mg per day.

The present composition preferably comprises 1-40 wt. % DHA based ontotal fatty acids, preferably 3-36 wt. % DHA based on total fatty acids,more preferably 10-30 wt. % DHA based on total fatty acids. The presentcomposition preferably comprises 0.5-20 wt. % EPA based on total fattyacids, preferably 2-10 wt. % EPA based on total fatty acids, morepreferably 5-10 wt. % EPA based on total fatty acids. Theabove-mentioned amounts take into account and optimize several aspects,including taste (e.g. too high LCP levels reduce taste, resulting in areduced compliance).

The present composition preferably contains at least one oil selectedfrom fish oil, algae oil and eggs lipids. Preferably the presentcomposition contains fish oil comprising DHA and EPA.

The ratio of the weights of DHA to EPA is preferably larger than 1, morepreferably 2:1 to 10:1, more preferably 3:1 to 8:1. The above-mentionedratios and amounts take into account and optimize several aspects,including taste (too high LCP levels reduce taste, resulting in areduced compliance), balance between DHA and precursors thereof toensure optimal effectiveness while maintaining low-volume formulations.

Sources of DHA possible sources of DHA: tuna oil, (other) fish oils, DHArich alkyl esters, algae oil, egg yolk, or phospholipids enriched withn-3 LCPUFA e.g. phosphatidylserine-DHA.

The present composition preferably contains a very low amount ofarachidonic acid (AA). Preferably the weight ratio DHA/AA in the presentcomposition is at least 5, preferably at least 10, more preferably atleast 15, preferably up to e.g. 30 or even up to 60. The present methodpreferably comprises the administration of a composition comprising lessthan 5 wt. % arachidonic acid based on total fatty acids, morepreferably below 2.5 wt. %, e.g. down to 0.5 wt %.

The weight ratio omega-6/omega-3 fatty acids in the present product ispreferably below 0.5, more preferably below 0.2, e.g. down to 0.05 or to0.01. The ratio ω-6/ω-3 fatty acids (C 20 and higher) in the presentproduct is preferably below 0.3, more preferably below 0.15, e.g. downto 0.06 or to 0.03.

Saturated and Monounsaturated Fatty Acids

The present composition preferably comprises saturated and/ormono-unsaturated fatty acids. The amount of saturated fatty acids ispreferably 6-60 wt. % based on total fatty acids, preferably 12-40 wt.%, more preferably 20-40 wt. % based on total fatty acids. In particularthe amount of C14:0 (myristic acid)+C16:0 (palmitic acid) is preferably5-50 wt. %, preferably 8-36 wt. %, more preferably 15-30 wt. %, based ontotal fatty acids. The total amount of monounsaturated fatty acids, suchas oleic acid and palmitoleic acid, is preferably between 5 and 40 wt.%, more preferably between 15 and 30 wt. %. A composition with thesepreferred amounts was found to be very effective.

Phospholipids

Preferably, the present composition preferably comprises phospholipids,preferably 0.1-50 wt. % phospholipids based on total weight of lipids,more preferably 0.5-20 wt. %, more preferably between 1 and 10% wt. %,most preferably between 1 and 5 wt. % based on total weight of lipids.The total amount of lipids is preferably between 10 and 30 wt. % on drymatter, and/or between 2 and 10 g lipid per 100 ml for a liquidcomposition. The composition preferably comprises between 0.01 and 1gram lecithin per 100 ml, more preferably between 0.05 and 0.5 gramlecithin per 100 ml. A composition with these preferred amounts wasfound to be very effective. In one embodiment, the phospholipidscomprise at least two phospholipids selected from the group consistingof phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositoland phosphatidylserine, preferably at least PC and PE. In a preferredembodiment, the phospholipids optionally present in the compositioncontain insignificant amounts (i.e at most in trace amounts, preferablybelow detection limits) of any of the above-identified PCs.

Vitamins C, E

Vitamin C, or a functional equivalent thereof, may be present in anamount to provide a daily dosage in the range of 20 to 2000 mg, inparticular in the range of 30 to 500 mg, more in particular in the rangeof 75 to 150 mg. In one embodiment, vitamin C, or a functionalequivalent thereof, is present in an amount in the range of 20 to 2000mg, in particular in the range of 30 to 500 mg, more in particular inthe range of 75 to 150 mg per 100 ml of the composition.

Tocopherol and/or an equivalent thereof (i.e. a compound having vitaminE activity) may be present in an amount to provide a daily dosage in therange of 10 to 300 mg, in particular in the range of 30 to 200 mg, morein particular in the range of 35 to 100 mg, to prevent oxidative damageresulting from dietary PUFA. In one embodiment, tocopherol and/orequivalent is present in an amount in the range of 10 to 300 mg, inparticular in the range of 30 to 200 mg, more in particular in the rangeof 35 to 100 mg per 100 ml of the composition. The term “tocopheroland/or an equivalent thereof”, and ‘alpha-TE’, as used in thisdescription, comprises tocopherols, tocotrienols, pharmaceutical and/ornutritional acceptable derivatives thereof and any combination thereof.The above numbers are based on tocopherol equivalents, recognized in theart.

Selenium

The present composition preferably contains selenium, because of itsantioxidant activity. Preferably the present method provides theadministration of a composition comprising 0.01 and 5 mg selenium per100 ml liquid product, preferably 0.02 and 0.1 mg selenium per 100 mlliquid product. The amount of selenium administered per day ispreferably more than 0.01 mg, more preferably 0.01 to 0.5 mg.

Protein

Although the composition may further comprise proteinaceous material, ithas been found that such component is not deemed necessary. In fact, itis thus possible to concentrate the actives in a low volume composition.Should a protein fraction be included, the protein fraction comprisesintact proteins, peptides as may be obtained by hydrolyses of intactproteins and by syntheses, derivatives of peptides comprising more than80 weight % amino acids. Nitrogen from nucleosides material and cholinewill not be calculated as being protein.

In one embodiment, it is preferred that the amount of taurine (includingtaurine salts) is less than 0.1 g, preferably less than 0.05 g per dailydose. Additionally or alternatively, it is preferred that the amount oftaurine (including taurine salts) is less than 5 mg, more preferablyless than 2.5 g per 100 g composition.

In one embodiment, the composition comprises less than 25 mg, morepreferably less than 20 mg, most preferably less than 15 mg cysteine andtaurine per 100 ml of the (liquid) composition. In one embodiment, thecomposition comprises less than 25 mg, more preferably less than 20 mg,most preferably less than 15 mg cysteine per 100 ml of the (liquid)composition. It is preferred that the protein fraction comprises morethan 70 weight % of casein or caseinates, or hydrolyzates thereof, andmore preferably 80 weight % or more, because caseins comprise relativelylow amounts of cysteine compared to other protein sources. It is furtherpreferred to heat the liquid composition in order to oxidize thecysteine molecules present in the protein. This impairs biologicalavailability of any residual cysteine as present in the formula. Apreferred heat treatment involves sterilization. It is preferred tomaintain the temperature remains below 135° C., preferably less than132° C. combined with a sufficient long time to have the cysteineoxidized, i.e. more than 30 seconds, preferably more than 40 seconds.

In one embodiment, it is preferred that the composition has a proteincontent of less than 15 en %, more preferably less than 10 en %, mostpreferably less than 5 en % of the total energy content of thecomposition. The energy percentages of the components are calculatedusing the calculation factors 9 kcal per g lipid, 4 kcal per g proteinor g digestible carbohydrates, 2 kcal per g dietary fibers and zero kcalfor the other components in the composition. In one embodiment, it ispreferred that the composition comprises less than 0.5 to 10 g proteinper 100 ml, more preferably less than 1 to 6 gram protein per 100 ml,most preferably 2 to 6 gram protein/100 ml.

Preferably the composition comprising B vitamin(s) further comprises oneor more of DHA, EPA, a uridine source (preferably UMP), phospholipids,choline, vitamin E, vitamin C, selenium. More preferably the compositioncomprises vitamin B12, vitamin B6 and folic acid, a uridine source(preferably UMP), and more preferably also DHA, EPA, phospholipids,choline, vitamin E, vitamin C, selenium.

A preferred composition according to the invention comprises, per dailydose or per 100 ml composition:

-   -   0.5-10000 μg, preferably 0.5-1000 μg vitamin B12,    -   0.5-100 mg, preferably 0.7-20 mg vitamin B6,    -   100-5000 μg, preferably 150-1000 μg folic acid,    -   100-500 mg, preferably 200-400 mg EPA,    -   900-1500 mg, preferably 950-1300 mg DHA,    -   50-600 mg, preferably 60-200 mg phospholipids,    -   200-600 mg, preferably 300-500 mg choline,    -   400-800 mg, preferably 500-700 mg UMP (uridine monophosphate),    -   20-60 mg, preferably 30-50 mg vitamin E (alpha-TE),    -   60-100 mg, preferably 60-90 mg vitamin C, and    -   40-80 μg, preferably 45-65 μg selenium.

More preferred, a composition according to the invention comprises per100 ml composition:

-   -   0.5-10000 μg, preferably 0.5-1000 μg vitamin B12,    -   0.5-100 mg, preferably 0.7-20 mg vitamin B6,    -   100-5000 μg, preferably 150-1000 μg folic acid,    -   100-500 mg, preferably 200-400 mg EPA,    -   900-1500 mg, preferably 950-1300 mg DHA,    -   50-600 mg, preferably 60-200 mg phospholipids,    -   200-600 mg, preferably 300-500 mg choline,    -   400-800 mg, preferably 500-700 mg UMP (uridine monophosphate),    -   20-60 mg, preferably 30-50 mg vitamin E (alpha-TE),    -   60-100 mg, preferably 60-90 mg vitamin C, and    -   40-80 μg, preferably 45-65 μg selenium.

The compositions as described above can be used as a nutritionaltherapy, nutritional support, as a medical food, as a food for specialmedical purposes or as a nutritional supplement. Such product can beconsumed at one, two or three servings between 75 and 200 ml per day orper unit, most preferably between 90 and 150 ml/day, most preferablyabout 125 mL per day in the aforementioned applications.

The subjects that can benefit from the method and composition of theinvention often experience problems with eating. Their sensorycapabilities and/or control of muscles can become imparted, as well asin some instances their ambition to apply proper eating habits.Swallowing and/or mastication may be problematic. Hence, the presentcomposition is preferably provided in the form of a drink capable ofbeing ingested through a straw.

Related therewith, the composition according to the invention preferablyhas a low viscosity, preferably a viscosity between 1 and 2000 mPa·smeasured at a shear rate of 100 sec-1 at 20° C., more preferably aviscosity between 1 and 100 mPa·s measured at a shear rate of 100 sec-1at 20° C. In a preferred embodiment the present composition has aviscosity of 1-80 mPa·s at a shear rate of 100 per sec at 20° C., morepreferably of 1-40 mPa·s at a shear rate of 100 per sec at 20° C. Theseviscosity measurements may for instance be performed using plate andcone geometry.

To be optimally accepted by the subject, the present compositionpreferably has an osmolality of 300 to 800 mOsm/kg. However, the energydensity of the product is preferably not so high that it interferes withnormal eating habits. When in liquid form, the present productpreferably contains between 0.2 and 3 kcal/ml, more preferably between0.5 and 2, between 0.7 and 1.5 kcal/ml.

In one aspect, the invention pertains to a method for preventing ortreating impaired plasma polar lipid levels, preferably phospholipidlevels in a preclinical AD or MCI subject or a subject with a highlikelihood of developing AD or MCI, comprising:

-   -   a) analyzing plasma levels of at least one phospholipid in a        subject;    -   b) selecting a subject having an impaired plasma phospholipid        level, preferably an impaired plasma polar lipid level,        preferably impaired plasma phosphatidylcholine level, preferably        an impaired plasma level of one or more PC species selected from        the group consisting of phosphatidylcholine diacyl C36:6 [PC aa        C36:6], PC aa C38:0, PC aa C38:6, PC aa C40:6 and PC acyl-alkyl        C40:6 [PC ae C40:6];    -   c) administering to said selected subject a composition        comprising at least one, preferably at least two, most        preferably all B vitamins selected from the group consisting of        vitamin B6, vitamin B12 and vitamin B9, and optionally one or        more of uridine and cytidine, or salts, phosphates, acyl        derivatives or esters thereof.

In a further aspect, the invention pertains to a composition for use inpreventing or treating impaired plasma polar lipid levels, preferablyphospholipid levels, more preferably plasma levels of one or more of theaforementioned polar lipid species, more preferably of one or more ofthe aforementioned PC species in a preclinical AD or MCI subject or asubject with a high likelihood of developing AD or MCI, wherein saidsubject is administered with a composition comprising at least one,preferably at least two, most preferably all B vitamins selected fromthe group consisting of vitamin B6, vitamin B12 and vitamin B9.

EXAMPLES Example 1a: Liquid Product Containing Per 125 ml Serving

Fat, g 4.9 Vitamin E (alpha-TE), mg 40 EPA, mg 300 Vitamin C, mg 80 DHA,mg 1200 Selenium, μg 60 Phospholipids, mg 106* Vitamin B12, μg 3Choline, mg 400 Vitamin B6, mg 1 UMP (uridine monophosphate), mg 625Folic acid, μg 400 Abbreviations: EPA, eicosapentaenoic acid; DHA,docosahexaenoic acid; TE, tocopherol equivalents; *Source: Lecithin.Does not contain significant amount of phosphatidylcholine diacyl C36:6[PC aa C36:6], PC aa C38:0, PC aa C38:6, PC aa C40:6 and PC acyl-alkylC40:6 [PC ae C40:6]

Example 1b: Liquid Product Containing Per 125 ml Serving

Energy, kcal 125 Calcium, mg 100 Protein, g 3.8 Phosphorus, mg 87.5Carbohydrate, g 16.5 Magnesium, mg 25.0 Fat, g 4.9 Iron, mg 2 EPA, mg300 Zinc, mg 1.5 DHA, mg 1200 Iodine, μg 16.3 Phospholipids, mg 106*Manganese, mg 0.41 Choline, mg 400 Copper, μg 225 UMP (uridinemonophosphate), mg 625 Molybdenum, μg 12.5 Vitamin E (alpha-TE), mg 40Chromium, μg 8.4 Vitamin C, mg 80 Vitamin A, μg 200 Selenium, μg 60Thiamin (B1), mg 0.19 Vitamin B12, μg 3 Riboflavin (B2), mg 0.20 VitaminB6, mg 1 Niacin (B3), mg NE 2.25 Folic acid, μg 400 Pantothenic acid(B5), mg 0.66 Sodium, mg 125 Vitamin D, μg 0.88 Potassium, mg 187.5Biotin, μg 5.0 Chloride, mg 156.3 Vitamin K, μg 6.6 Abbreviations: EPA,eicosapentaenoic acid; DHA, docosahexaenoic acid; TE, tocopherolequivalents; NE, niacin equivalents. *Source: lecithin. Does not containsignificant amounts of phosphatidylcholine diacyl C36:6 [PC aa C36:6],PC aa C38:0, PC aa C38:6, PC aa C40:6 and PC acyl-alkyl C40:6 [PC aeC40:6]

Example 2. Combined Dietary Folate, Vitamin B12, and Vitamin B6 IntakeIncreases Plasma Levels of Specific Polar Lipid Species Methods Animals

A total of 24 male Sprague-Dawley rats (Crl:CD(SD)) were obtained fromCharles River, Sulzfeld, Germany. Animals aged 6-8 weeks on arrival werehoused in groups in a temperature- and light-controlled room, under 12 hlight-12 h dark cycles. Rats had free access to food and water. Bodyweight was registered once a week. All animal experimental protocolswere conducted in accordance with international and national laws andinstitutional guidelines and approved by the local ethics committee,i.e. DEC Consult, Bilthoven, The Netherlands.

Diets

Two different diets with increasing folate, vitamin B12, and vitamin B6contents were used: 1) Bvitamin-poor; and 2) Bvitamin-normal. Diets wereAIN-93 M based [1], isoenergetic, and identical with respect to theirprotein, carbohydrate, fat, fiber, and mineral contents. All diets weredevoid of any measurable amounts of DHA. The vitamin mix (AIN-93-VX) [1]was prepared without folic acid, cyanocobalamin, and pyridoxine; thesevitamins were subsequently supplemented accordingly. Diets wereformulated with vitamin-free, ethanol-precipitated casein (HarlanTeklad, Madison, Wis., USA) and were manufactured by SsniffSpezialdiaten, Soest, Germany.

The Bvitamin-poor diet contained low amounts of folate (<0.1 mg/kg),vitamin B12 (<1.0 μg/kg), and vitamin B6 (<0.6 mg/kg). No sulfathiazoledrugs were added to the diet and therefore a limited amount of folatewas still expected to be provided by the gut flora. Vitamin B12deficiency in the rat is difficult to achieve because of considerableendogenous storage of this vitamin. To attain a moderate reduction ofendogenous vitamin B12, the Bvitamin-poor was supplemented with 50 g/kgpectin (polygalacturonic acid, high methoxyl, Obipektin®, NF/USP Citrus;TEFCO FoodIngredients, Bodegraven, The Netherlands), which binds vitaminB12 in the intestine, making it less bioavailable [2]. Pectinconsequently promotes depletion of endogenous vitamin B12 through theenterohepatic circulation the vitamin. Since pectin could affect foodintake [3], the two diets were supplemented with pectin to maintainuniform intakes of the diets. Pectin has minimal effects on vitamin B12status when the diet contains adequate amounts of this vitamin [2].

The vitamin B-normal diet provided 100% of the requirements for each ofthe three vitamins according to the National Research Council report onthe nutrient requirements of laboratory animals [4]. The exact dietarylevels of the three Bvitamins in each experimental diet are indicated inTable 1.

TABLE 1 Folate, vitamin B12, and vitamin B6 content of the experimentaldiets Calculated dietary levels % of Folate Vitamin B12 Vitamin B6 Dietrecommended (folic (cyanocobalamin) (pyridoxine- description levels [4]acid) mg/kg diet HCL) B vitamin:  ~0% <0.1 <0.001 <0.6 poor B vitamin:100% 1.0 0.05 6.0 normal

Experimental Design

Animals were randomized into the two experimental groups according totheir body weights at the start of the intervention period.Subsequently, rats were fed one of the two experimental diets for 4weeks.

Tissue Preparation

After the supplementation period, animals that had been feed-deprivedfor 3-4 hours were killed by inhalation of isoflurane vaporized inmedicinal air and subsequent decapitation by guillotine. Trunk blood wascollected through a funnel into EDTA-containing tubes. Aftercentrifugation at 1750×g for 10 min, plasma was aspirated for subsequentanalyses.

Plasma Polar Lipid Species

Plasma samples were analyzed for lipid profiles at the Kansas LipidomicsResearch Center using electrospray ionization tandem mass spectrometry(ESI-MS/MS).

Results

TABLE 2 Plasma concentrations of specific polar lipid species (μM)Parameter B vitamin poor B vitamin normal C20:4 CE 3150.15 4379.83 C22:6CE 59.62 85.53 ePC(36:5) 2.72 3.34 ePC(38:0) 2.12 3.39 ePC(38:6) 2.573.19 ePC(40:5) 2.08 2.61 ePC(40:6) 2.29 2.82 ePE(40:6) 0.65 0.68LPC(20:5) 0.78 1.18 LPC(22:6) 10.15 13.40 PC(36:5) 14.15 20.45 PC(36:6)1.08 1.51 PC(38:0) 1.32 1.68 PC(38:5) 108.78 167.22 PC(38:6) 82.80108.05 PC(40:6) 42.26 61.08 PC(40:7) 10.18 15.93 PI(40:5) 2.90 3.89PI(40:6) 2.75 3.48 C18:3 CE 33.48 73.39 ePC(38:4) 12.10 15.18 ePC(40:4)3.96 5.09 LPC(18:3) 1.55 2.22 LPC(20:4) 121.37 166.64 PC(38:4) 338.00497.76 PC(42:8) 1.05 1.51 C16:1 CE 113.17 232.96 ePC(36:0) 0.43 0.51ePC(38:5) 7.79 9.50 LPC(18:0) 122.02 150.90 LPC(22:5) 3.60 4.64 PC(36:1)26.42 35.94 PC(40:4) 4.92 6.75 PC(40:5) 18.06 24.29 PC(40:8) 7.99 13.63PC(42:10) 1.06 1.91 PC(42:6) 0.76 1.01 PC(42:7) 0.87 1.23 PC(42:9) 0.881.29 PI(34:1) 0.96 2.02 PI(38:4) 77.68 94.58 PI(38:5) 4.50 6.23

The plasma concentrations of these specific polar lipid speciesmonitored could be increased significantly using increased amounts of Bvitamins.

Example 3. Combined Dietary Folate, Vitamin B12, and Vitamin B6 IntakeIncreases Plasma Levels of Specific Polar Lipid Species Methods Animals

A total of 24 male Sprague-Dawley rats (Crl:CD(SD)) were obtained fromCharles River, Sulzfeld, Germany. Animals aged 6-8 weeks on arrival werehoused in groups in a temperature- and light-controlled room, under 12 hlight-12 h dark cycles. Rats had free access to food and water. Bodyweight was registered once a week. All animal experimental protocolswere conducted in accordance with international and national laws andinstitutional guidelines and approved by the local ethics committee,i.e. DEC Consult, Bilthoven, The Netherlands.

Diets

Two different diets with increasing folate, vitamin B12, and vitamin B6contents were used: 1) Bvitamin-poor and 2) Bvitamin-enriched. Dietswere AIN-93 M based [1], isoenergetic, and identical with respect totheir protein, carbohydrate, fat, fiber, and mineral contents. All dietswere devoid of any measurable amounts of DHA. The vitamin mix(AIN-93-VX) [1] was prepared without folic acid, cyanocobalamin, andpyridoxine; these vitamins were subsequently supplemented accordingly.Diets were formulated with vitamin-free, ethanol-precipitated casein(Harlan Teklad, Madison, Wis., USA) and were manufactured by SsniffSpezialdiaten, Soest, Germany.

The Bvitamin-poor diet contained low amounts of folate (<0.1 mg/kg),vitamin B12 (<1.0 μg/kg), and vitamin B6 (<0.6 mg/kg). No sulfathiazoledrugs were added to the diet and therefore a limited amount of folatewas still expected to be provided by the gut flora. Vitamin B12deficiency in the rat is difficult to achieve because of considerableendogenous storage of this vitamin. To attain a moderate reduction ofendogenous vitamin B12, the Bvitamin-poor was supplemented with 50 g/kgpectin (polygalacturonic acid, high methoxyl, Obipektin®, NF/USP Citrus;TEFCO FoodIngredients, Bodegraven, The Netherlands), which binds vitaminB12 in the intestine, making it less bioavailable [2]. Pectinconsequently promotes depletion of endogenous vitamin B12 through theenterohepatic circulation the vitamin. Since pectin could affect foodintake [3], all two diets were supplemented with pectin to maintainuniform intakes of the diets. Pectin has minimal effects on vitamin B12status when the diet contains adequate amounts of this vitamin [2].

The vitamin B-enriched diet provided 400% of the requirements for eachof the three vitamins according to the National Research Council reporton the nutrient requirements of laboratory animals [4]. The exactdietary levels of the three Bvitamins in each experimental diet areindicated in Table 1.

TABLE 3 Folate, vitamin B12, and vitamin B6 content of the experimentaldiets Calculated dietary levels % of Folate Vitamin B12 Vitamin B6 Dietrecommended (folic (cyanocobalamin) (pyridoxine- description levels [4]acid) mg/kg diet HCL) B vitamin:  ~0% <0.1 <0.001 <0.6 poor B vitamin:400% 4.0 0.20 24.0 enriched

Experimental Design

Animals were randomized into the two experimental groups according totheir body weights at the start of the intervention period.Subsequently, rats were fed one of the two experimental diets for 4weeks.

Tissue Preparation

After the supplementation period, animals that had been feed-deprivedfor 3-4 hours were killed by inhalation of isoflurane vaporized inmedicinal air and subsequent decapitation by guillotine. Trunk blood wascollected through a funnel into EDTA-containing tubes. Aftercentrifugation at 1750×g for 10 min, plasma was aspirated for subsequentanalyses.

Plasma Polar Lipid Species

Plasma samples were analyzed for lipid profiles at the Kansas LipidomicsResearch Center using electrospray ionization tandem mass spectrometry(ESI-MS/MS).

Results

TABLE 4 Plasma concentrations of specific polar lipid species (μM)Parameter B vitamin poor B vitamin enriched C20:4 CE 3150.15 4826.03C22:6 CE 59.62 108.71 ePC(36:5) 2.72 3.38 ePC(38:0) 2.12 3.29 ePC(38:6)2.57 3.63 ePC(40:5) 2.08 2.91 ePC(40:6) 2.29 3.09 ePE(40:6) 0.65 0.74LPC(20:5) 0.78 0.95 LPC(22:6) 10.15 14.46 PC(36:5) 14.15 18.46 PC(36:6)1.08 1.60 PC(38:0) 1.32 1.77 PC(38:5) 108.78 166.63 PC(38:6) 82.80115.60 PC(40:6) 42.26 63.91 PC(40:7) 10.18 16.91 PI(40:5) 2.90 4.41PI(40:6) 2.75 4.46 C18:3 CE 33.48 58.44 ePC(38:4) 12.10 15.95 ePC(40:4)3.96 5.22 LPC(18:3) 1.55 1.91 LPC(20:4) 121.37 162.49 PC(38:4) 338.00490.03 PC(42:8) 1.05 1.63 C16:1 CE 113.17 206.93 ePC(36:0) 0.43 0.52ePC(38:5) 7.79 10.13 LPC(18:0) 122.02 142.51 LPC(22:5) 3.60 5.26PC(36:1) 26.42 32.92 PC(40:4) 4.92 6.46 PC(40:5) 18.06 25.97 PC(40:8)7.99 12.89 PC(42:10) 1.06 2.09 PC(42:6) 0.76 1.08 PC(42:7) 0.87 1.36PC(42:9) 0.88 1.35 PI(34:1) 0.96 1.44 PI(38:4) 77.68 99.89 PI(38:5) 4.506.20

The plasma concentrations of these specific polar lipid speciesmonitored could be increased significantly using increased amounts of Bvitamins.

Example 4. Combined Dietary Folate, Vitamin B12, and Vitamin B6 IntakeIncreases Plasma Levels of Specific Polar Lipid Species Methods Animals

A total of 24 male Sprague-Dawley rats (Crl:CD(SD)) were obtained fromCharles River, Sulzfeld, Germany. Animals aged 6-8 weeks on arrival werehoused in groups in a temperature- and light-controlled room, under 12 hlight-12 h dark cycles. Rats had free access to food and water. Bodyweight was registered once a week. All animal experimental protocolswere conducted in accordance with international and national laws andinstitutional guidelines and approved by the local ethics committee,i.e. DEC Consult, Bilthoven, The Netherlands.

Diets

Two different diets with increasing folate, vitamin B12, and vitamin B6contents were used: 1) Bvitamin-poor and 2) Bvitamin-high. Diets wereAIN-93 M based [1], isoenergetic, and identical with respect to theirprotein, carbohydrate, fat, fiber, and mineral contents. All diets weredevoid of any measurable amounts of DHA. The vitamin mix (AIN-93-VX) [1]was prepared without folic acid, cyanocobalamin, and pyridoxine; thesevitamins were subsequently supplemented accordingly. Diets wereformulated with vitamin-free, ethanol-precipitated casein (HarlanTeklad, Madison, Wis., USA) and were manufactured by SsniffSpezialdiaten, Soest, Germany.

The Bvitamin-poor diet contained low amounts of folate (<0.1 mg/kg),vitamin B12 (<1.0 μg/kg), and vitamin B6 (<0.6 mg/kg). No sulfathiazoledrugs were added to the diet and therefore a limited amount of folatewas still expected to be provided by the gut flora. Vitamin B12deficiency in the rat is difficult to achieve because of considerableendogenous storage of this vitamin. To attain a moderate reduction ofendogenous vitamin B12, the Bvitamin-poor was supplemented with 50 g/kgpectin (polygalacturonic acid, high methoxyl, Obipektin®, NF/USP Citrus;TEFCO FoodIngredients, Bodegraven, The Netherlands), which binds vitaminB12 in the intestine, making it less bioavailable [2]. Pectinconsequently promotes depletion of endogenous vitamin B12 through theenterohepatic circulation the vitamin. Since pectin could affect foodintake [3], all two diets were supplemented with pectin to maintainuniform intakes of the diets. Pectin has minimal effects on vitamin B12status when the diet contains adequate amounts of this vitamin [2].

The vitamin B-high diet provided 1600%, respectively, of therequirements for each of the three vitamins according to the NationalResearch Council report on the nutrient requirements of laboratoryanimals [4]. The exact dietary levels of the three Bvitamins in eachexperimental diet are indicated in Table 1.

TABLE 5 Folate, vitamin B12, and vitamin B6 content of the experimentaldiets Calculated dietary levels % of Folate Vitamin B12 Vitamin B6 Dietrecommended (folic (cyanocobalamin) (pyridoxine- description levels [4]acid) mg/kg diet HCL) B vitamin:  ~0% <0.1 <0.001 <0.6 poor B vitamin:1600% 16.0 0.80 96.0 high

Experimental Design

Animals were randomized into the two experimental groups according totheir body weights at the start of the intervention period.Subsequently, rats were fed one of the two experimental diets for 4weeks.

Tissue Preparation

After the supplementation period, animals that had been feed-deprivedfor 3-4 hours were killed by inhalation of isoflurane vaporized inmedicinal air and subsequent decapitation by guillotine. Trunk blood wascollected through a funnel into EDTA-containing tubes. Aftercentrifugation at 1750×g for 10 min, plasma was aspirated for subsequentanalyses.

Plasma Polar Lipid Species

Plasma samples were analyzed for lipid profiles at the Kansas LipidomicsResearch Center using electrospray ionization tandem mass spectrometry(ESI-MS/MS).

Results

TABLE 6 Plasma concentrations of specific polar lipid species (μM)Parameter B vitamin poor B vitamin high C20:4 CE 3150.15 5727.49 C22:6CE 59.62 132.26 ePC(36:5) 2.72 3.85 ePC(38:0) 2.12 3.53 ePC(38:6) 2.573.83 ePC(40:5) 2.08 3.17 ePC(40:6) 2.29 3.71 ePE(40:6) 0.65 0.97LPC(20:5) 0.78 1.08 LPC(22:6) 10.15 17.81 PC(36:5) 14.15 18.27 PC(36:6)1.08 1.66 PC(38:0) 1.32 2.01 PC(38:5) 108.78 174.86 PC(38:6) 82.80131.48 PC(40:6) 42.26 78.73 PC(40:7) 10.18 17.80 PI(40:5) 2.90 5.13PI(40:6) 2.75 4.58 C18:3 CE 33.48 59.77 ePC(38:4) 12.10 18.68 ePC(40:4)3.96 5.81 LPC(18:3) 1.55 2.12 LPC(20:4) 121.37 182.45 PC(38:4) 338.00588.56 PC(42:8) 1.05 1.73 C16:1 CE 113.17 181.77 ePC(36:0) 0.43 0.67ePC(38:5) 7.79 11.48 LPC(18:0) 122.02 172.13 LPC(22:5) 3.60 6.62PC(36:1) 26.42 37.50 PC(40:4) 4.92 7.52 PC(40:5) 18.06 32.10 PC(40:8)7.99 15.16 PC(42:10) 1.06 2.56 PC(42:6) 0.76 1.29 PC(42:7) 0.87 1.43PC(42:9) 0.88 1.65 PI(34:1) 0.96 1.64 PI(38:4) 77.68 107.27 PI(38:5)4.50 6.20

The plasma concentrations of these specific polar lipid speciesmonitored could be increased significantly using increased amounts of Bvitamins.

REFERENCES

-   1. Reeves P G, Nielsen F H, Fahey G C Jr: “AIN-93 purified diets for    laboratory rodents: final report of the American Institute of    Nutrition ad hoc writing committee on the reformulation of the    AIN-76A rodent diet”. J Nutr 1993, 123:1939-1951.-   2. Cullen R W, Oace S M: “Dietary pectin shortens the biologic    half-life of vitamin B12 in rats by increasing fecal and urinary    losses” J Nutr 1989, 119:1121-1127.-   3. Hove E L, King S: “Effects of pectin and cellulose on growth,    feed efficiency, and protein utilization, and their contribution to    energy requirement and cecal VFA in rats” J Nutr 1979,    109:1274-1278.-   4. National Research Council: Nutrient requirements of laboratory    animals, Fourth Revised Edition edn. Washington: National Academic    Press; 1995.

Example 5. Clinical Study

In the present intervention plasma concentrations of a selected range ofphosphatidylcholine [PC] species were monitored. The study was a24-week, randomized, controlled, double-blind study, conducted at 27study centers. Drug-naïve patients with mild AD (MMSE scores ≥20) anddiagnosis of probable AD according to the NINCDS-ADRDA criteria, wererandomly assigned (1:1) to the composition including the componentsaccording to table 3, or an iso-caloric control product. The duration ofintervention was 24 weeks.

TABLE 7 Nutritional composition used in Example 5 clinical trialcomponent Amount per daily dose* EPA 300 mg DHA 1200 mg Phospholipids**106 mg Choline 400 mg UMP 625 mg Vitamin E (alpha-TE) 40 mg Vitamin C 80mg Selenium 60 μg Vitamin B12 3 μg Vitamin B6 1 mg Folic acid 400 μg*125 ml, daily dose. TE = tocopherol equivalents. **Source: Lecithin.Does not contain significant amount of phosphatidylcholine diacyl C36:6[PC aa C36:6], PC aa C38:0, PC aa C38:6, PC aa C40:6 and PC acyl-alkylC40:6 [PC ae C40:6]

Baseline and 24-week plasma samples of the subjects taking theintervention product were analyzed for plasma polar lipid profile at theKansas Lipidomics Research Center using electrospray ionization tandemmass spectrometry (ESI-MS/MS). Phospholipid concentrations were comparedbetween baseline and 24 weeks using T-test comparison. Only polar lipidspecies showing significant increase from baseline or significantdecrease from baseline are reported.

Results Plasma Polar Lipid Concentrations

The polar lipid plasma concentrations at baseline and at 24 weeks aregiven in Table 8.

TABLE 8 Plasma polar lipid concentration (nM; mean ± s.d.) in subjectstaking the intervention product (n = 47) at baseline and after 24 weeksof intervention. Intervention product Polar lipid Baseline 24-weekEffect C20:4 CE 1094.03 1208.72 Increase C22:6 CE 116.16 280.76 IncreaseePC(36:5) 10.11 11.52 Increase ePC(38:0) 2.86 4.57 Increase ePC(38:6)6.61 10.54 Increase ePC(40:5) 8.26 9.08 Increase ePC(40:6) 4.67 7.94Increase ePE(40:6) 0.58 0.99 Increase LPC(20:5) 0.77 1.39 IncreaseLPC(22:6) 1.37 2.65 Increase PC(36:5) 28.64 49.32 Increase PC(36:6) 1.622.28 Increase PC(38:0) 4.89 6.32 Increase PC(38:5) 50.43 59.98 IncreasePC(38:6) 70.71 151.85 Increase PC(40:6) 26.84 60.42 Increase PC(40:7)5.74 8.67 Increase PI(40:5) 0.83 1.03 Increase PI(40:6) 1.17 2.81Increase C16:0 CE 466.57 528.01 Increase C18:2 CE 6298.16 6782.25Increase C20:5 CE 233.35 557.18 Increase C22:5 CE 9.75 11.24 IncreaseDSM(18:0) 1.79 2.52 Increase ePC(32:1) 4.43 4.67 Increase ePC(32:2) 0.780.90 Increase ePC(34:0) 1.58 1.80 Increase ePE(38:6) 0.95 1.44 IncreaseLPE(22:6) 0.62 1.11 Increase PA(34:3) 0.33 0.36 Increase PC(44:2) 0.330.39 Increase PE(36:0) 0.34 0.49 Increase PE(38:0) 0.40 0.78 IncreasePE(38:6) 5.02 8.09 Increase PE(40:6) 3.22 5.56 Increase PE(40:7) 0.841.24 Increase PI(38:6) 0.55 1.18 Increase SM(16:0) 270.43 290.29Increase SM(18:0) 57.27 60.67 Increase SM(22:0) 3.09 5.06 IncreaseSM(24:0) 58.11 63.47 Increase SM(24:1) 151.66 168.89 Increase C19:0 CE12.29 9.31 Decrease C19:1 CE 121.39 76.09 Decrease C20:0 CE 90.66 49.23Decrease C20:1 CE 48.22 28.72 Decrease C20:3 CE 136.94 124.01 DecreaseePC(36:1) 14.03 11.42 Decrease ePC(38:l) 8.83 8.36 Decrease ePC(38:2)9.50 8.19 Decrease ePC(38:3) 11.70 6.78 Decrease ePC(40:2) 3.48 3.00Decrease ePC(40:3) 5.59 3.35 Decrease LPC(20:3) 1.84 1.41 DecreasePC(34:3) 17.58 14.23 Decrease PC(36:3) 133.07 110.74 Decrease PC(38:1)1.51 1.02 Decrease PC(38:2) 3.94 1.83 Decrease PC(40:3) 1.89 1.31Decrease PE(34:1) 1.53 1.10 Decrease PE(34:2) 2.45 1.75 DecreasePE(36:1) 1.23 1.04 Decrease PE(36:2) 7.23 5.57 Decrease PE(36:3) 2.201.47 Decrease PE(36:4) 3.56 2.64 Decrease PE(38:3) 0.74 0.49 DecreasePE(38:4) 8.96 6.56 Decrease PE(40:4) 0.39 0.33 Decrease PE(40:5) 0.690.52 Decrease PI(36:3) 1.97 1.57 Decrease PI(38:3) 4.77 4.00 DecreasePS(38:4) 0.95 0.55 Decrease

CONCLUSIONS

Overall, the plasma concentrations of specific polar lipids monitoredover the intervention period, showed a significant increase after takingthe intervention product for 24 weeks (see table 8). Concentrations ofother specific polar lipids decrease as a result of the interventionproduct. These results indicate that specific polar lipids can beincreased and other specific polar lipids can be decreased byintervention product as claimed in the invention.

1. A method for treating a preclinical subject with Alzheimer's Disease(AD) or mild cognitive impairment (MCI), wherein the treatment resultsin inhibiting, suppressing, and/or decreasing impaired plasmaphosphatidylcholine (PC) or phosphatidylethanolamine (PE) lipid levels,the method comprising administering to the subject a compositioncomprising at least one B vitamin selected from the group consisting ofvitamin B6, vitamin B12 and vitamin B9.
 2. The method according to claim1, wherein the composition comprises at least two B vitamins selectedfrom the group consisting of vitamin B6, vitamin B12 and vitamin B9. 3.The method according to claim 2, wherein the composition comprisesvitamin B6, vitamin B12 and vitamin B9.
 4. The method according to claim1, wherein the composition comprises per daily dosage or per 100 ml, atleast one of: 0.5-10000 μg vitamin B12; 0.5-100 mg vitamin B6; and100-5000 μg folic acid.
 5. The method according to claim 4, wherein thecomposition comprises per daily dosage or per 100 ml: 0.5-10000 μgvitamin B12; 0.5-100 mg vitamin B6; and 100-5000 μg folic acid.
 6. Themethod according to claim 3, wherein the composition comprises per dailydosage or per 100 ml, 0.5-100 mg vitamin B6, and 100-5000 μg folic acid.7. The method according to claim 1, wherein the plasmaphosphatidylcholine (PC) or phosphatidylethanolamine (PE) lipids are ofone or more polar lipids selected from the group consisting of C16:1 CE;C18:3 CE; C20:4 CE; PI(34:1); PI(38:2); PI(38:4); C16:0 CE; C18:2 CE;PA(34:3); PE(36:0); PE(38:0); aePC(36:0); aePC(38:0); aePC(38:4);aePC(40:4); 1PC(18:0); 1PC(18:3); 1PC(20:4); PC(36:1); PC(38:0);PC(38:4); PC(40:4); DSM(18:0); aePC(32:1); aePC(32:2); aePC(34:0);PC(44:2); SM(16:0); SM(18:0); SM(22:0); SM(24:0); SM(24:1); aePC(36:5);aePC(38:5); aePC(40:5); 1PC(20:5); 1PC(22:5); PC(36:5); PC(38:5);PC(40:5); PI(38:5); PI(40:5); C20:5 CE; C22:6 CE; aePC(38:6);aePC(40:6); aePE(40:6); PC(36:6); PC(38:6); PC(40:6); PC(42:6);PI(40:6); C22:5 CE; aePE(38:6); 1PE(22:6); PE(38:6); PE(40:6); PI(38:6);PC(40:7); PC(40:8); PC(42:10); PC(42:7); PC(42:8); PC(42:9); PE(40:7);1PC(22:6); C19:0 CE; C19:1 CE; C20:0 CE; C20:1 CE; C20:3 CE; PE(34:1);PE(34:2); PE(36:1); PE(36:2); PE(36:3); PE(36:4); PE(38:3); PE(38:4);PE(40:4); PI(36:3); PI(38:3); PS(38:4); aePC(36:1); aePC(38:1);aePC(38:2); aePC(38:3); aePC(40:2); aePC(40:3); 1PC(20:3); PC(34:3);PC(36:3); PC(38:1); PC(38:2); PC(40:3); PE(40:5) 1PC 22:6; and/or PC40:6.
 8. The method according to claim 1, wherein the compositionfurther comprises one or more of uridine and cytidine, or salts,phosphates, acyl derivatives or esters thereof.
 9. The method accordingto claim 1, wherein the composition further comprises a lipid fractioncomprising at least one of docosahexaenoic acid (22:6; DHA),eicosapentaenoic acid (20:5; EPA) and docosapentaenoic acid (22:5; DPA),or esters thereof.
 10. The method according claim 1, wherein thecomposition further comprises, per daily dose or per 100 ml composition,at least 500 mg of DHA, and at least 50 mg of uridine, calculated as thecumulative amount of uridine, deoxyuridine, uridine phosphates,nucleobase uracil and acylated uridine.
 11. The method according claim1, wherein the composition comprises, per daily dose or per 100 mlcomposition: 0.5-10000 μg vitamin B12; 0.5-100 mg vitamin B6; 100-5000μg folic acid; 100-500 mg EPA, 1000-1500 mg DHA, 50-600 mgphospholipids, 200-600 mg choline, 400-800 mg UMP (uridinemonophosphate), 20-60 mg vitamin E (alpha-TE), 60-100 mg vitamin C, and40-80 μg selenium.
 12. The method according claim 1, wherein the subjectis an elderly of at least 50 years of age, and not suffering from anycognitive deficits.
 13. A method for treating a preclinical AD or MCIsubject, wherein the treatment results in inhibiting, suppressing,and/or decreasing impaired plasma levels of one or morephosphatidylcholines (PCs) selected from the group consisting ofphosphatidylcholine diacyl C36:6 [PC aa C36:6], phosphatidylcholinediacyl C38:0 [PC aa C38:0], phosphatidylcholine diacyl C38:6 [PC aaC38:6], phosphatidylcholine diacyl C40:6 [PC aa C40:6] andphosphatidylcholine acyl-alkyl C40:6 [PC ae C40:6], the methodcomprising administering to the subject a comprising at least one Bvitamin selected from the group consisting of vitamin B6, vitamin B12and vitamin B9.
 14. The method according to claim 13, wherein thecomposition comprises at least two B vitamins selected from the groupconsisting of vitamin B6, vitamin B12 and vitamin B9.
 15. The methodaccording to claim 14, wherein the composition comprises vitamin B6,vitamin B12 and vitamin B9.
 16. The method according to claim 13,wherein the one or more phosphatidylcholines are at least twophosphatidylcholine species selected from the group consisting ofphosphatidylcholine diacyl C36:6 [PC aa C36:6], phosphatidylcholinediacyl C38:0 [PC aa C38:0], phosphatidylcholine diacyl C38:6 [PC aaC38:6], phosphatidylcholine diacyl C40:6 [PC aa C40:6] andphosphatidylcholine acyl-alkyl C40:6 [PC ae C40:6].
 17. The methodaccording to claim 13, wherein the one or more phosphatidylcholinespecies is selected from the group consisting of phosphatidylcholinediacyl C36:6 [PC aa C36:6], phosphatidylcholine diacyl C38:6 [PC aaC38:6], phosphatidylcholine diacyl C40:6 [PC aa C40:6] andphosphatidylcholine acyl-alkyl C40:6 [PC ae C40:6].
 18. The methodaccording to claim 17, wherein the polar lipids are phosphatidylcholinediacyl C40:6 [PC aa C40:6] and/or phosphatidylcholine acyl-alkyl C40:6[PC ae C40:6].
 19. The method according to claim 13, wherein the plasmaPC levels are monitored in the subject before and/or afteradministration.
 20. A method for treating a preclinical AD or MCIsubject, wherein the treatment results in inhibiting, suppressing,and/or decreasing impaired plasma polar lipid levels in a subject with ahigh likelihood of developing AD or MCI, comprising: (a) analyzingplasma levels of at least one plasma polar lipid in a subject, whereinthe plasma polar lipid is a phosphatidylcholine (PC) orphosphatidylethanolamine (PE) lipid; (b) selecting a subject having animpaired plasma level of one or more of the plasma polar lipids; (c)administering to the selected subject a composition comprising at leastone B vitamin selected from the group consisting of vitamin B6, vitaminB12 and vitamin B9.
 21. The method according to claim 20, wherein thecomposition comprises vitamin B6, vitamin B12 and vitamin B9.
 22. Themethod according to claim 20, wherein the composition further comprisesone or more of uridine and cytidine, or salts, phosphates, acylderivatives or esters thereof.
 23. The method according to claim 20,wherein the plasma polar lipid is selected from the group consisting ofC16:1 CE; C18:3 CE; C20:4 CE; PI(34:1); PI(38:2); PI(38:4); C16:0 CE;C18:2 CE; PA(34:3); PE(36:0); PE(38:0); aePC(36:0); aePC(38:0);aePC(38:4); aePC(40:4); 1PC(18:0); 1PC(18:3); 1PC(20:4); PC(36:1);PC(38:0); PC(38:4); PC(40:4); DSM(18:0); aePC(32:1); aePC(32:2);aePC(34:0); PC(44:2); SM(16:0); SM(18:0); SM(22:0); SM(24:0); SM(24:1);aePC(36:5); aePC(38:5); aePC(40:5); 1PC(20:5); 1PC(22:5); PC(36:5);PC(38:5); PC(40:5); PI(38:5); PI(40:5); C20:5 CE; C22:6 CE; aePC(38:6);aePC(40:6); aePE(40:6); PC(36:6); PC(38:6); PC(40:6); PC(42:6);PI(40:6); C22:5 CE; aePE(38:6); 1PE(22:6); PE(38:6); PE(40:6); PI(38:6);PC(40:7); PC(40:8); PC(42:10); PC(42:7); PC(42:8); PC(42:9); PE(40:7);1PC(22:6); C19:0 CE; C19:1 CE; C20:0 CE; C20:1 CE; C20:3 CE; PE(34:1);PE(34:2); PE(36:1); PE(36:2); PE(36:3); PE(36:4); PE(38:3); PE(38:4);PE(40:4); PI(36:3); PI(38:3); PS(38:4); aePC(36:1); aePC(38:1);aePC(38:2); aePC(38:3); aePC(40:2); aePC(40:3); 1PC(20:3); PC(34:3);PC(36:3); PC(38:1); PC(38:2); PC(40:3); and PE(40:5).